Condensed indoline derivatives and their use as 5HT, in particular 5HT2C, receptor ligands

ABSTRACT

A chemical compound of formula (I) wherein R 1  and R 2  are independently selected from hydrogen and alkyl; R 3  is alkyl; R 4  and R 5  are selected from hydrogen and alkyl; R 6  and R 7  are independently selected from hydrogen, halogen, hydroxyl, alkyl, aryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, alkylthio, alkylsulfoxyl, nitro, carbonitrile, carbo-alkoxy, carbo-aryloxy and carboxyl; and A is a 5- or 6-membered ring optionally containing one or more heteroatoms wherein the atoms of the ring A, other than the unsaturated carbon atoms of the phenyl ring to which the ring A is fused, are saturated or unsaturated, and pharmaceutically acceptable salts, addition compounds and prodrugs thereof; and the use thereof in therapy, particularly as an agonist or antagonist of a 5HT receptor, particularly a 5HT 2C  receptor, for instance in the treatment of disorders of the central nervous system; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes insipidus, and sleep apnea, and particularly for the treatment of obesity.

The present invention relates to indoline derivatives, to processes andintermediates for their preparation, to pharmaceutical compositionscontaining them and to their medicinal use. The active compounds of thepresent invention are useful in treating obesity and other disorders.

It has been recognised that obesity is a disease process influenced byenvironmental factors in which the traditional weight loss methods ofdieting and exercise need to be supplemented by therapeutic products (S.Parker, “Obesity: Trends and Treatments”, Scrip Reports, PJBPublications Ltd, 1996).

Whether someone is classified as overweight or obese is generallydetermined on the basis of their body mass index (BMI) which iscalculated by dividing body weight (kg) by height squared (m²). Thus,the units of BMI are kg/m² and it is possible to calculate the BMI rangeassociated with minimum mortality in each decade of life. Overweight isdefined as a BMI in the range 25-30 kg/m², and obesity as a BMI greaterthan 30 kg/M². There are problems with this definition in that it doesnot take into account the proportion of body mass that is muscle inrelation to fat (adipose tissue). To account for this, obesity can alsobe defined on the basis of body fat content: greater than 25% and 30% inmales and females, respectively.

As the BMI increases there is an increased risk of death from a varietyof causes that is independent of other risk factors. The most commondiseases with obesity are cardiovascular disease (particularlyhypertension), diabetes (obesity aggravates the development ofdiabetes), gall bladder disease (particularly cancer) and diseases ofreproduction. Research has shown that even a modest reduction in bodyweight can correspond to a significant reduction in the risk ofdeveloping coronary heart disease.

Compounds marketed as anti-obesity agents include Orlistat (Reductil®)and Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorptiondirectly and tends to produce a high incidence of unpleasant (thoughrelatively harmless) side-effects such as diarrhoea. Sibutramine (amixed 5-HT/noradrenaline reuptake inhibitor) can increase blood pressureand heart rate in some patients. The serotonin releaser/reuptakeinhibitors fenfluramine (Pondimin®) and dexfenfluramine (Redux™) havebeen reported to decrease food intake and body weight over a prolongedperiod (greater than 6 months). However, both products were withdrawnafter reports of preliminary evidence of heart valve abnormalitiesassociated with their use. There is therefore a need for the developmentof a safer anti-obesity agent.

The non-selective ⁵-HT_(2C) receptor agonists/partial agonistsm-chlorophenylpiperazine (mCPP) and trifluoromethylphenylpiperazine(TFMPP) have been shown to reduce food intake in rats (G. A. Kennett andG. Curzon, Psychopharmacol., 1988, 98, 93-100; G. A. Kennett, C. T.Dourish and G. Curzon, Eur. J. Pharmacol., 1987, 141, 429-453) and toaccelerate the appearance of the behavioural satiety sequence (S. J.Kitchener and C. T. Dourish, Psychopharmacol., 1994, 113, 369-377).Recent findings from studies with mCPP in normal human volunteers andobese subjects have also shown decreases in food intake. Thus, a singleinjection of mCPP decreased food intake in female volunteers (A. E. S.Walsh et al., Psychopharmacol., 1994, 116, 120-122) and decreased theappetite and body weight of obese male and female subjects duringsubchronic treatment for a 14 day period (P. A. Sargeant et al.,Psychopharmacol., 1997, 113, 309-312). The anorectic action of mCPP isabsent in 5-HT_(2C) receptor knockout mutant mice (L. H. Tecott et al.,Nature, 1995, 374, 542-546) and is antagonised by the 5-HT_(2C) receptorantagonist SB-242084 in rats (G. A. Kennett et al., Neuropharmacol.,1997, 36, 609-620). It seems therefore that mCPP decreases food intakevia an agonist action at the 5-HT_(2C) receptor.

Other compounds which have been proposed as 5-HT_(2C) receptor agonistsfor use in the treatment of obesity include the substituted 1-aminoethylindoles disclosed in EP-A-0655440. CA-2132887 and CA-2153937 disclosethat tricyclic 1-aminoethylpyrrole derivatives and tricyclic1-aminoethyl pyrazole derivatives bind to 5-HT_(2C) receptors and may beused in the treatment of obesity. WO-A-98/30548 disclosesaminoalkylindazole compounds as 5-HT_(2C) agonists for the treatment ofCNS diseases and appetite regulation disorders. WO 9517405 disclosesmethods for the preparation of indolines for use as melatonin receptorligands.

It is an object of this invention to provide selective, directly acting5HT₂ receptor ligands for use in therapy and particularly for use asanti-obesity agents. It is a further object of this invention to providedirectly acting ligands selective for 5-HT_(2B) and/or 5-HT_(2C)receptors, for use in therapy and particularly for use as anti-obesityagents. It is a further object of this invention to provide selective,directly acting 5-HT_(2C) receptor ligands, preferably 5-HT_(2C)receptor agonists, for use in therapy and particularly for use asanti-obesity agents.

According to the present invention there is provided a chemical compoundof formula (I):

wherein:

-   R₁ and R₂ are independently selected from hydrogen and alkyl;-   R₃ is alkyl;-   R₄ and R₅ are selected from hydrogen and alkyl;-   R₆ and R₇ are independently selected from hydrogen, halogen,    hydroxy, alkyl, aryl, amino, alkylamino, dialkylamino, alkoxy,    aryloxy, alkylthio, alkylsulfoxyl, alkylsulfonyl, nitro,    carbonitrile, carbo-alkoxy, carbo-aryloxy and carboxyl; and-   A is a 5- or 6-membered ring optionally containing one or more    heteroatoms wherein the atoms of the ring A, other than the    unsaturated carbon atoms of the phenyl ring to which the ring A is    fused, are saturated or unsaturated,-   and pharmaceutically acceptable salts, addition compounds and    prodrugs thereof.

As used herein, the term “alkyl” means a branched or unbranched, cyclicor acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl)hydrocarbyl radical. Where cyclic, the alkyl group is preferably C₃ toC₁₂, more preferably C₅ to C₁₀. Where acyclic, the alkyl group ispreferably C₁ to C₁₀, more preferably C₁ to C₆, more preferably methyl,ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl ortertiary-butyl) or pentyl (including n-pentyl and iso-pentyl), morepreferably methyl. It will be appreciated therefore that the term“alkyl” as used herein includes alkyl (branched or unbranched), alkenyl(branched or unbranched), alkynyl (branched or unbranched), cycloalkyl,cycloalkenyl and cycloalkynyl.

As used herein, the term “lower alkyl” means a branched or unbranched,cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl)hydrocarbyl radical, wherein a cyclic lower alkyl group is C₅, C₆ or C₇,and wherein an acyclic lower alkyl group is methyl, ethyl, propyl(n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl),more preferably methyl.

As used herein, the term “aryl” means an aromatic group, such as phenylor naphthyl, or a heteroaromatic group containing one or moreheteroatom(s), such as pyridyl,pyrrolyl, quinolinyl, furanyl, thienyl,oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl,triazolyl, imidazolyl or pyrimidinyl.

As used herein, the term “alkoxy” means alkyl—O—. As used herein, theterm “aryloxy” means aryl—O—.

As used herein, the term “halogen” means a fluorine, chlorine, bromineor iodine radical, preferably a fluorine or chlorine radical.

As used herein the term “prodrug” means any pharmaceutically acceptableprodrug of the compound of formula (I) which is metabolised in vivo to acompound of formula (I).

As used herein, the term “pharmaceutically acceptable salt” means anypharmaceutically acceptable salt of the compound of formula (I). Saltsmay be prepared from pharmaceutically acceptable non-toxic acids andbases including inorganic and organic acids and bases. Such acidsinclude acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,dichloroacetic, ethanesulfonic, formic, fumaric, gluconic, glutamic,hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic andthe like. Particularly preferred are fumaric, hydrochloric, hydrobromic,phosphoric, succinic, sulfuric and methanesulfonic acids, andparticularly fumaric acid. Acceptable base salts include alkali metal(e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium)and aluminium salts.

As used herein, the term “addition compound” means any pharmaceuticallyacceptable addition compound of the compound of formula (I). Additioncompounds include those which are formed without change of valency fromthe union between a compound of formula (I) and one or more othermolecules, particularly solvates, hydrates and inclusion complexes (suchas cyclodextrin complexes).

As used herein, the term “A is a 5- or 6-membered ring” refers to a ringcontaining 5 or 6 ring atoms in total, i.e. including the carbon atomsin the unsaturated positions of the phenyl ring to which A is fused.

Where any of R₁ to R₇ is an alkyl group or an alkyl-containing group(such as alkoxy, alkylamino or alkylthio, for instance) as defined informula (I) above, then that alkyl group, cr the alkyl group of thealkyl-containing group, may be substituted or unsubstituted. Whereeither R₆ or R₇ is an aryl group or an aryl-containing group (such asaryloxy, for instance) as defined in formula (I), then said aryl group,or the aryl group of the aryl-containing group, may be substituted orunsubstituted. The ring A may be substituted or unsubstituted. Where anyof R₁ to R₇ or A is substituted, there will generally be 1 to 3substituents present, preferably 1 substituent. Substituents mayinclude:

-   carbon-containing groups such as    -   alkyl,    -   aryl, (e.g. substituted and unsubstituted phenyl),    -   arylalkyl; (e.g. substituted and unsubstituted benzyl);-   halogen atoms and halogen containing groups such as    -   haloalkyl (e.g. trifluoromethyl),    -   haloaryl (e.g. chlorophenyl);-   oxygen containing groups such as    -   alcohols (e.g. hydroxy, hydroxyalkyl, hydroxyaryl,        (aryl)(hydroxy)alkyl),    -   ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl,        alkoxyaryl, aryloxyaryl),    -   aldehydes (e.g. carboxaldehyde),    -   ketones (e.g. alkylcarbonyl, arylcarbonyl, alkylcarbonylalkyl,        alkylcarbonylaryl, arylcarbonylalkyl, arylcarbonylaryl,        arylalkylcarbonyl, arylalkylcarbonylalkyl,        arylalkylcarbonylaryl)    -   acids (e.g. carboxy, carboxyalkyl, carboxyaryl),    -   acid derivatives such as esters        -   (e.g. alkoxycarbonyl aryloxycarbonyl, alkoxycarbonylalkyl,            aryloxycarbonylalkyl, alkoxycarbonylaryl,            aryloxycarbonylaryl, alkylcarbonyloxy,            alkylcarbonyloxyalkyl),        -   amides        -   (e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl,            aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl,            arylaminocarbonyl or arylalkylaminocarbonyl,            alkylcarbonylamino, arylcarbonylamino or            arylalkylcarbonylamino),        -   carbamates        -   (eg. alkoxycarbonylamino, aryloxycarbonylamino,            arylalkyloxycarbonylamino, aminocarbonyloxy, mono- or            di-alkylaminocarbonyloxy, arylaminocarbonyloxy or            arylalkylamninocarbonyloxy)        -   and ureas        -   (eg. mono- or di-alkylaminocarbonylamino,            arylaminocarbonylamino or arylalkylaminocarbonylamino);-   nitrogen containing groups such as    -   amines (e.g. amino, mono- or dialkylamino, arylamino,        aminoalkyl, mono- or dialkylaminoalkyl),    -   azides,    -   nitriles (e.g. cyano, cyanoalkyl),    -   nitro;-   sulfur containing groups such as    -   thiols, thioethers, sulfoxides, and sulfones        -   (e.g. alkylthio, alkylsulfinyl, alkylsulfonyl,            alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,            arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl,            arylsulfinylalkyl, arylsulfonylalkyl)-   and heterocyclic groups containing one or more, preferably one,    heteroatom,    -   -   (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,            thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl,            thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl,            pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,            tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl,            pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl,            morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl,            indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl,            7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl,            quinolinyl, isoquinolinyl, naphthridinyl, cinnolinyl,            quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl,            chromenyl, chromanyl, isochromanyl, phthalazinyl and            carbolinyl).

In the compounds of formula (I), preferably R₁ and R₂ are independentlyselected from hydrogen and lower alkyl (preferably acyclic lower alkyland more preferably methyl), and preferably from hydrogen. Where R₁ andR₂ are selected from alkyl, it is preferred that said alkyl groups areunsubstituted.

Preferably, the compounds of formula (I) are selected from compounds inwhich R₁ is the same as R₂. Preferably, R₁ and R₂ are both hydrogen.

The compounds of formula (I) are selected from compounds in which R₃ isalkyl, preferably lower alkyl, more preferably acyclic lower alkyl, andmost preferably methyl.

R₄ and R₅ are independently selected from hydrogen and alkyl (includingcycloalkyl, halo-alkyl (such as trifluoromethyl) and arylalkyl).Preferably R₄ and R₅ are independently selected from hydrogen andloweralkyl, more preferably from hydrogen and acyclic lower alkyl, andmost preferably hydrogen.

R₆ and R₇ are preferably independently selected from hydrogen, halogen,hydroxy, alkyl (including cycloalkyl, halo-alkyl (such astrifluoromethyl) and arylalkyl), aryl, alkoxy (including arylalkoxy),aryloxy, alkylthio, alkylsulfoxyl and alkylsulfonyl. Preferably, R₆ andR₇ are independently selected from hydrogen and alkyl, more preferablyfrom hydrogen and lower alkyl, more preferably from hydrogen and acycliclower alkyl, and preferably from hydrogen.

It will be understood that the ring A may be a partially unsaturatedring (including a partially unsaturated heterocyclic ring) or anaromatic ring (including a heteroaromatic ring). As noted above, thering A may be substituted or unsubstituted. Where substituted, thesubstituent group may be present on a carbon atom of the ring or, wherethe ring a contains one or more heteroatom(s) and where the valency ofthe heteroatom allows substitution, on a heteroatom of the ring.

As noted herein, the term “partially unsaturated ring” refers to a ringwhich contains unsaturated ring atoms and one or more double bonds butwhich is not aromatic, for example a cyclopentenyl or cyclohexenyl ring.It will be appreciated therefore that a partially unsaturated ring A maycontain one double bond, i.e. the double bond between the unsaturatedcarbon atoms of the phenyl ring to which the ring A is fused, in whichcase the atoms of the ring A, other than the carbon atoms in theunsaturated positions of the phenyl ring to which A is fused, aresaturated. Alternatively, a partially unsaturated ring A may contain anadditional double bond provided that this additional double bond doesnot result in the ring A being aromatic.

Where A contains one or more heteroatom(s), it is preferred that theheteroatoms are selected from N, O and S. In one embodiment, theheteroatom(s) are selected from O and S. Where A contains one or moreheteroatom(s), preferably A contains one or two heteroatom(s) andpreferably only one heteroatom.

In one embodiment, where A contains heteroatom(s) then A is partiallyunsaturated.

In a further embodiment, where A is aromatic then A contains noheteroatoms.

Preferably A is partially unsaturated.

It is preferred that A is a 5-membered ring, particularly a 5-memberedpartially unsaturated ring.

It is preferred that A is partially unsaturated, preferably wherein theatoms of the ring A, other than the unsaturated carbon atoms of thephenyl ring to which the ring A is fused, are saturated.

In one embodiment, the compounds of formula are selected from compoundswherein A is a 5-membered partially unsaturated carbocyclic ring or a5-membered heterocyclic ring (preferably partially unsaturated), andpreferably from compounds wherein A is a 5-membered partiallyunsaturated heterocyclic ring (preferably wherein the heteroatom(s) ofthe ring are O or S, particularly O).

In a further embodiment the compounds of formula (I) are selected fromcompounds wherein A is selected from the group consisting ofcyclohexenyl, cyclopentenyl, phenyl, dihydrofuranyl, dihydropyranyl,dihydrothienyl 2,3-dihydro-1,4-dioxin and tetrahydropyridinyl (includingN-acetyltetrahydropyridinyl).

The compounds of the invention may contain one or more asymmetric carbonatoms, so that the compounds can exist in different stereoisomericforms. The compounds can be, for example, racemates or optically activeforms. The optically active forms can be obtained by resolution of theracemates or by asymmetric synthesis. In a preferred embodiment of theinvention, the preferred stereochemistry at the carbon atom to which R₃and NR₁R₂ are bound is(S).

In one embodiment of the invention, the compounds are preferablyselected from:

-   (S)-1-(benz[g]indolin-1-yl)-2-propylamine,-   (R)-1-(benz[g]indolin-1-yl)-2-propylamine,-   (S)-1-(2,3,7,8-tetrahydrofuro[2,3-g]indol-1-yl)-2-propylamine,-   (S)-1-(2,3,7,8-tetrahydro-9H-pyrano[2,3-g]indol-1-yl)-2-propylamine,-   (S)-1-(2,3,7,8-tetrahydrothieno[2,3-g]indol-1-yl)-2-propylamine,-   (S)-1-(2,3,7,8-tetrahydro-9H-1,4-dioxino[2,3-g]indol-9-yl)-2-propylamine,-   (S)-1-(2,3,6,7,8,9-hexahydro-1H-benz[g]indol-1-yl)]-2-propylamine,-   (S)-1-[1-(1,2,3,6,7,8-hexahydrocyclopent[g]indolyl)]-2-propylamine,-   [2S,3′(R or    S)]-1-(3-ethyl-2,3,7,8-tetrahydrofuro[2,3-g]indol-1-yl)-2-propylamine,-   [2S,3′(S or    R)]-1-(3-Ethyl-2,3,7,8-tetrahydrofuro[2,3-g]indol-1-yl)-2-propylamine    and-   (S)-2-[6-(acetyl)-1-(2,3,6,7,8,9-hexahydro-pyrrolo[2,3-f]quinolinyl)]-2-propylamine.

In a preferred embodiment of the invention, the compounds are selectedfrom:

-   (S)-1-(benz[g]indolin-1-yl)-2-propylamine,-   (S)-1-(2,3,7,8-tetrahydrofuro[2,3-g]indol-1-yl)-2-propylamine,-   (S)-1-(2,3,7,8-tetrahydrothieno[2,3-g]indol-1-yl)-2-propylamine,-   (S)-1-(2,3,7,8-tetrahydro-9H-pyrano[2,3-g]indol-1-yl)-2-propylamine,-   (S)-1-[1-(1,2,3,6,7,8-hexahydrocyclopent[g]indolyl)]-2-propylamine,-   [2S,3(R or    S)]-1-(3-ethyl-2,3,7,8-tetrahydrofuro[2,3-g]indol-1-yl)-2-propylamine    and-   [2S,3(S or    R)]-1-(3-ethyl-2,3,7,8-tetrahydrofuro[2,3-g]indol-1-yl)-2-propylamine,-   and more preferably from    (S)-1-(2,3,7,8-tetrahydrofuro[2,3-g]indol-1-yl)-2-propylamine and    (S)-1-[1- (1,2,3,6,7,8-hexahydrocyclopent[g]indolyl)]-2-propylamine.

According to a further aspect of the invention, there is provided acompound of formula (I) for use in therapy.

The compounds of formula (I) may be used in the treatment (includingprophylactic treatment) of disorders associated with 5-HT₂ receptorfunction. The compounds may act as receptor agonists or antagonists,preferably receptor agonists. Preferably, the compounds may be used inthe treatment (including prophylactic treatment) of disorders associatedwith 5-HT_(2B) and/or 5-HT_(2C) receptor function. Preferably, thecompounds may be used in the treatment (including prophylactictreatment) of disorders where 5-HT_(2C) receptor activity is required,and preferably where a 5-HT_(2C) receptor agonist is required.

The compounds of formula (I) may be used in the treatment or preventionof central nervous disorders such as depression, atypical depression,bipolar disorders, anxiety disorders, obsessive-compulsive disorders,social phobias or panic states, sleep disorders, sexual dysfunction,psychoses, schizophrenia, migraine and other conditions associated withcephalic pain or other pain, raised intracranial pressure, epilepsy,personality disorders, age-related behavioural disorders, behaviouraldisorders associated with dementia, organic mental disorders, mentaldisorders in childhood, aggressivity, age-related memory disorders,chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia,anorexia nervosa or premenstrual tension; damage of the central nervoussystem such as by trauma, stroke, neurodegenerative diseases or toxic orinfective CNS diseases such as encephalitis or meningitis;cardiovascular disorders such as thrombosis; gastrointestinal disorderssuch as dysfunction of gastrointestinal motility; diabetes insipidus;and sleep apnea.

According to a further aspect of the invention, there is provided use ofa compound of formula (I) in the manufacture of a medicament for thetreatment (including prophylaxis) of the above-mentioned disorders. In apreferred embodiment, there is provided use of a compound of formula (I)in the manufacture of a medicament for the treatment (includingprophylaxis) of obesity.

According to a further aspect of the invention, there is provided amethod of treating a disorder selected from the group consisting of theabove-mentioned disorders comprising administering to a patient in needof such treatment an effective dose of a compound of formula (I). In apreferred embodiment, there is provided a method of treatment (includingprophylaxis) of obesity.

According to a further aspect of the invention, there is provided apharmaceutical composition comprising a compound of formula (I) incombination with a pharmaceutically acceptable carrier or excipient anda method of making such a composition comprising combining a compound offormula (I) with a pharmaceutically acceptable carrier or excipient.

According to a further aspect of the invention, there is provided amethod of preparing a compound of formula (I), for instance in themanner described below in Reaction Scheme 1. R₁ to R₇ are as previouslydefined.

The N-alkylindole (III) may be formed by reaction of the indole (II)with an appropriate carbamylethylsulfonate in the presence of a strongbase such as potassium hydroxide in a solvent such as methyl sulfoxide.Where required, the N-alkylindole (IV) may be obtained from theN-alkylindole (III) by reaction with an acylating agent eg. aceticanhydride in the presence of an acid catalyst followed by treatment witha reducing agent eg. diborane in a solvent such as THF. The indoline (V)may be obtained via reduction of the N-alkylindole (IV) with a reducingagent such as sodium cyanoborohydride or tetrabutylammonium borohydridein a solvent such as acetic acid or dichloromethane. The indoline (I)(R₁=R₂=H) may be obtained by reaction of the indoline (V) with a reagentsuitable to reveal the protected amine function.

The compounds of formula (I) (R₁ and/or R₂=alkyl) may be prepared fromcompounds of formula (I) (R₁=R₂=H) by standard methods such as reductivealkylation with an appropriate aldehyde or ketone in the presence of areducing agent such as sodium triacetoxyborohydride, formic acid orsodium cyanoborohydride.

If, in any of the other processes mentioned herein, any of thesubstituent groups R₁ to R₇ is other than the one required, thesubstituent group may be converted to the desired substituent by knownmethods. The substituents R₁ to R₇ may also need protecting against theconditions under which the reaction is carried out. In such a case, theprotecting group may be removed after the reaction has been completed.

The processes described above may be carried out to give a compound ofthe invention in the form of a free base or as an acid addition salt. Ifthe compound of the invention is obtained as an acid addition salt, thefree base can be obtained by basifying a solution of the acid additionsalt. Conversely, if the product of the process is a free base, an acidaddition salt may be obtained by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts frombasic compounds.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) transdermal or rectal administration orin a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g. magnesium stearate,talc or silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulfate). The tabletsmay be coated by methods well known in the art. Liquid preparations fororal administration may take the form of, for example, solutions, syrupsor suspensions, or they may be presented as a dry product forconstitution with water or other suitable vehicle before use. Suchliquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (eg. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters or ethyl alcohol); and preservatives (e.g.methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form e.g. in ampoules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilising and/or dispersing agents.

Alternatively, the active ingredient may be in powder form forreconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (e.g., obesity) is 0.1 to500 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

The invention will now be described in detail with reference to thefollowing examples. It will be appreciated that the invention isdescribed by way of example only and modification of detail may be madewithout departing from the scope of the invention.

EXPERIMENTAL Assay Procedures

1. Binding to Serotonin Receptors

The binding of compounds of formula (I) to serotonin receptors wasdetermined in vitro by standard methods. The preparations wereinvestigated in accordance with the assays given hereinafter.

Method (a): For the binding to the 5-HT_(2C) receptor the 5-HT_(2C)receptors were radiolabeled with [³H]-5-HT. The affinity of thecompounds for 5-HT_(2C) receptors in a CHO cell line was determinedaccording to the procedure of D. Hoyer, G. Engel and H. O. Kalkman,European J. Pharmacol., 1985, 118, 13-23.

Method (b): For the binding to the 5-HT_(2B) receptor the 5-HT_(2B)receptors were radiolabeled with [³H]-5-HT. The affinity of thecompounds for human 5-HT_(2B) receptors in a CHO cell line wasdetermined according to the procedure of K. Schmuck, C. Ullmer, P.Engels and H. Lubbert, FEBS Lett., 1994, 342, 85-90.

Method (c): For the binding to the 5-HT_(2A) receptor the 5-HT_(2A)receptors were radiolabeled with [¹²⁵I]-DOI. The affinity of thecompounds for 5-HT_(2A) receptors in a HO cell line was determinedaccording to the procedure of D. J. McKenna and S. J. Peroutka, J.Neurosci., 1989, 9/10, 3482-90.

The thus-determined activity of compounds of formula (I) is shown inTable 1. TABLE 1 Compound K_(I) (2C) K_(I) (2B) K_(I) (2A) 1 107 39 1736 70 218 2232. Functional Activity

The functional activity of compounds of formula (I) was assayed using aFluorimetric Imaging Plate reader (FLIPR) in the following manner.

CHO cells expressing either the h5-HT_(2C) or h5-HT_(2A) receptors werecounted and plated into standard 96 well microtitre plates before theday of testing to give a confluent monolayer. The following day thecells were dye loaded with the calcium sensitive dye Fluo 3-AM byincubation with-serum free culture maintenance media containing pluronicacid and Fluo 3-AM dissolved in DMSO at 37° C. in a CO₂ incubator at 95%humidity for approximately 90 minutes. Unincorporated dye was removed bywashing with Hanks balanced salt solution containing 20 mM HEPES and 2.5mM probenecid (the assay buffer) using an automated cell washer to leavea total volume of 100 μl/well.

The drug (dissolved in 50 μl of assay buffer) was added at a rate of 70μl/sec to each well of the FLIPR 96 well plate during fluorescencemeasurements. The measurements are taken at 1 sec intervals and themaximum fluorescent signal was measured (approx 10-15 secs after drugaddition) and compared with the response produced by 10 μM 5-HT (definedas 100%) to which it is expressed as a percentage response (relativeefficacy). Dose response curves were constructed using Graphpad Prism(Graph Software Inc.).

The thus determined activities of the compounds of formula (I) is shownin Table 2. TABLE 2 h5-HT_(2A) h5-HT_(2C) Relative Relative CompoundEC₅₀ (nM) Efficacy (%) EC₅₀ (nM) Efficacy (%) 1 1374 51 158 79 2 >10 000— 1720 44 3 138 81 6 94 4 505 66 47 89 5 48 77 0.4 86 6 312 71 47 90 71835 14 440 68 8 10000 0 217 69 9 1143 22 50 74 10 403 15 51 67

Synthetic Examples Example 1

(S)1-(Benz[g]indolin-1-yl)-2-propylamine hemi-fumarate

(S)-1-[2-(tert-Butoxycarbonylamino)propyl]-benz[g]indole

Benz[g]indole (1.5 g, 10 mmol) (Bartoli et al., Tetrahedron Lett., 1989,30(16), 2129-32) was added portionwise to a stirred suspension ofpowdered potassium hydroxide (85%, 4.8 g, 72 mmol) in methyl sulfoxide(50 mL). The mixture was warmed to 35° C. and stirred for 30 min. Asolution of (S)-2-(tert-butoxycarbonylamino)propane methanesulfonate(11.4 g, 45 mmol) in methyl sulfoxide (20 mL) was added over 2 h. Themixture was stirred for 20 h and partitioned between water (100 mL) andether (3×50 mL). The combined organic extracts were washed with brine(2×), dried (magnesium sulfate), concentrated in vacuo and purified bycolumn chromatography [SiO₂; heptane-ethyl acetate (3:1)] to give theproduct (0.7 g, 12%) as a white solid: IR ν_(max) (Nujol)/cm⁻¹ 1686,1529, 1366, 1176, 1058, 804 and 685; NMR δ_(H) (400 MHz, CDCl₃) 1.19(3H, d, J 5.5 Hz), 1.54 (9H, s), 3.96-4.05 (1H, m), 4.36-4.51 (2H, m),4.91 (1H, brs), 6.59 (1H, t, J 3 Hz), 7.04 (1H, d, J 3 Hz), 7.39 (1H, d,J 8 Hz), 7.48 (1H, d, J 8 Hz), 7.55 (1H, t, J 7 Hz) 7.66 (1H, d, J 8.5Hz), 7.92 (1H, d, J 8.5 Hz) and 8.51 (1H, brs).

(S)-1-[2-(tert-Butoxycarbonylamino)propyl]-benz[g]indoline

To a stirred solution of(S)-1-[2-(tert-butoxycarbonylamino)propyl]-benz[g]indole (0.49 g, 1.5mmol) in acetic acid (10 mL) was added portionwise sodiumcyanoborohydride (95%, 0.30 g, 4.5 mmol). The mixture was stirred for 16h and partitioned between ether (40 mL) and saturated aqueous sodiumbicarbonate solution (3×50 mL). The organic layer was washed with brine(2 ×), dried (magnesium sulfate), concentrated in vacuo and purified bycolumn chromatography [SiO₂; heptane-ethyl acetate (6:1)) to give theproduct (0.24 g, 49%) as a pale yellow solid: IR ν_(max) (Nujol)/cm⁻¹1689, 1528, 1362, 1298, 1051 and 790; NMR δ_(H) (400 MHz, CDCl₃) 1.39(3H, d, J 6.5 Hz), 1.45 (9H, s), 3.11-3.28 (2H, m), 3.32-3.42 (2H, m),3.62-3.69 (2H, m), 3.98-4.08 (1H, m), 4.78 (1H, brs), 7.30-7.38 (1H, m),7.33-7.41 (3H, m), 7.72-7.81 (1H, m) and 7.98-8.01 (1H, m).

(S)-1-(Benz[g]indolin-1-yl)-2-propylamine hemi-fumarate

To a stirred solution of(S)-1-[2-(tert-butoxycarbonylamino)propyl)-benz[g]indoline (0.23 g, 0.7mmol) in dichloromethane (2 mL) was added dropwise trifluoroacetic acid(2 mL). The mixture was stirred for 1 h and partitioned between aqueoussodium hydroxide solution (2 M, 20 mL) and dichloromethane (3×20 mL).The combined organic extracts were washed with brine (2 ×), dried(magnesium sulfate) and concentrated in vacuo to give a pale yellow oil.The oil was dissolved in 2-propanol (5 mL) and the solution was heatedto boiling then fumaric acid (0.08 g, 0.7 mmol) was added. The mixturewas cooled to 0° C. and filtered. The filter-cake was dried in vacuo togive the product (0.13 g, 65%) as a white solid: mp. 205-207° C.; NMRδ_(H) (400 MHz, DMSO-d₆) 1.23 (3H, d, J 6.5 Hz), 3.01-3.69 (7H, m), 6.39(1H, s), 7.31-7.40 (4H, m), 7.83 (1H, m) and 8.06 (1H, m).

Example 2

(R)-1-(Benz[g]indolin-1-yl)2-propylamine hemi-fumarate

(R)-1-[2-(tert-Butoxycarbonylamino)propyl]-benz[g]indole

(R)-1-[2-(tert-Butoxycarbonylamino)propyl]-benz[g]indole was preparedaccording to the method described in Example 1 using benz[g]indole and(R)-2-(tert-butoxycarbonylamino)propane methanesulfonate to give theproduct (0.69 g, 35%) as a pale yellow solid: IR ν_(max) (Nujol)/cm⁻¹1686, 1529, 1467, 1176, 1058, 804 and 722; NMR δ_(H) (400 MHz CDCl₃)1.15 (3H, d, J 7 Hz), 1.41 (9H, s), 4.16-4.28 (1H, m), 4.38-4.49 (2H,m), 4.91 (1H, brs), 6.59 (1H, d, J 3 Hz), 7.04 (1H, d, J 3 Hz), 7.40(1H, t, J 7 Hz), 7.49 (1H, d, J 8.5 Hz), 7.55 (1H, t, J 7 Hz), 7.68 (1H,d, J 9 Hz), 7.91 (1H, d, J 8 Hz) and 8.50 (1H, brs).

(R)-1-[2-(tert-Butoxycarbonylamino)propyl]-benz[g]indoline

(R)-1-[2-(tert-Butoxycarbonylamino)propyl]-benz[g]indoline was preparedaccording to the method described in Example 1 from(R)-1-[2-(tert-butoxycarbonylamino)propyl]-benz[g]indole to give theproduct (0.14 g, 28%) as a pale yellow solid: IR ν_(max) (Nujol)/crm⁻¹1689, 1528, 1362, 1298, 1169, 1051 and 789; NMR δ_(H) (400 MHz, CDCl₃)1.34 (3H, d, J 7.5 Hz), 1.41 (9H, s), 3.07-3.23 (2H, m), 3.27-3.35 (2H,m), 3.56-3.62 (2H, m), 3.95-4.03 (1H, m), 4.72 (1H, brs), 7.21-7.24 (1H,m), 7.28-7.35 (3H, m), 7.72 (1H, d, J 7.5 Hz) and 7.93 (1H, d, J7.5 Hz).

(R)-1-(6-(Benz[g]indolin-1-yl)-2-propylamine hemi-fumarate

(R)-1-(6-(Benz[g]indolin-1-yl)-2-propylamine hemi-fumarate was preparedaccording to the method described in Example 1 using(R)-1-[2-(tert-butoxycarbonylamino)propyl]-benz[g]indoline to give theproduct (0.12 g, 95%) as a white solid: mp. 205-207° C.; NMR δ_(H) (400MHz, DMSO-d₆) 1.24 (3H, d, J6.5 Hz), 3.01-3.69 (7H, m), 6.39 (1H, s),7:31-7.40 (4H, m), 7.83 (1H, m) and 8.06 (1H, m).

Example 3

(S)-1-(2,3,7,8-Tetrahydrofuro[2,3-g]indol-1-yl)-2-propylamine fumarate

2,3-Dihydrobenzo[b]furan-5-carboxaldehyde and2,3-dihydrobenzo[b]furan-7-carboxaldehyde

To a stirred solution of 2,3-dihydrobenzo[b]furan (9.4 mL, 83.4 mmol) indichloromethane (250 mL) under Ar at −5° C. was added dropwisetitanium(IV) chloride (18 mL, 167.0 mmol) over 15 min, maintaining thetemperature below 0° C. After addition was complete, the red-brownreaction mixture was allowed to stir for a further 10 min beforeα,α-dichloromethyl methyl ether (8.3 mL, 91.6 mmol) was added dropwise[CAUTION—exotherm] maintaining the temperature below 0° C. Upon completeaddition, the vivid crimson reaction mixture was allowed to warm toambient temperature over 2 h, and was then cautiously poured onto asaturated aqueous solution of sodium bicarbonate (700 mL). The mixturewas filtered through a pad of Kieselguhr, which was washed through withdichloromethane. The phases were separated and the aqueous phase wasextracted with dichloromethane (2×400 mL). The combined organicfractions were washed with brine (300 mL), dried (magnesium sulfate) andconcentrated in vacuo to afford a mixture [5-CHO:7-CHO (4:1)] ofaldehyde products (11.48 g, 93%) as a green-black liquid which as usedwithout further purification.

Methyl 2-azido-3-(2,3dihydrobenzo[b]furan-5-yl)propenate and methyl2-azido-3-(2,3-dihydrobenzo[b]furan-7-yl)propenate

To a stirred solution of potassium tert-butoxide (31.0 g, 0.26 mol) inanhydrous methanol (220 mL) under Ar at −13° C. was added dropwise amixture of methyl azidoacetate (31.7 g, 0.27 mol), and2,3-dihydrobenzo[b]furan-5-carboxaldehyde and2,3-dihydrobenzo[b]furan-7-carboxaldehyde (4:1 mixture; 10.15 g, 69mmol) over 40 min. After complete addition, the reaction mixture wasstirred at −10° C. for 1 h, then stored at 0° C. overnight (with a ventneedle in place).

The reaction mixture was partitioned between ethyl acetate (750 mL) andwater (1 L) and the aqueous phase was extracted with ethyl acetate(2×300 mL). The combined organic fractions were washed with brine (300mL), dried (magnesium sulfate) and concentrated in vacuo to afford acrude oil. Purification by flash column chromatography[SiO₂;dichloromethane-heptane (1:1)] afforded a mixture[5-substituted:7-substituted (4:1)] of products (11.4 g, 68%) as a paleyellow solid which was used without further purification.

Methyl 7,8-dihydrofuro[2,3-g]indole-2-carboxylate, methyl5,6-dihydrofuro[3,2-f]indole-2-carboxylate and methyl5,6-dihydrofuro[2,3-e]indole-2-carboxylate

To stirred xylenes (800 mL) under Ar at reflux was added dropwise asolution of methyl 2-azido-3-(2,3-dihydrobenzo[b]furan-5-yl)propenateand methyl 2-azido-3-(2,3-dihydrobenzo[b]furan-7-yl)propenate (4:1mixture; 11.4 g, 46.5 mmol) in xylenes (300 mL) over 3.5 h. Aftercomplete addition, the mixture was heated at reflux for a further 30min, followed by removal of xylenes (750 mL) by distillation. Theresidual solution was allowed to cool, with stirring, to ambienttemperature overnight.

The resultant precipitate was filtered and washed with cold xylenes toafford a mixture [(2,3-g):(3,2-f)-1:1] of products (5.90 g, 59%) as awhite solid which was used without further purification. The filtratewas concentrated in vacuo and the residue was recrystallised from hotxylenes (100 mL) to afford a mixture [(2,3-g):(3,2-f):(2,3-e)-12:48:40]of products (2.23 g, 22%) as a pale yellow solid.

7,8-Dihydrofuro[2,3-g]indole-2-carboxylic acid and5,6-dihydrofuro[3,2-f]indole-2-carboxylic acid

To a stirred suspension of methyl7,8-dihydrofuro[2,3-g]indole-2-carboxylate and methyl5,6-dihydrofuro[3,2-f]indole-2-carboxylate (1:1) (5.85 g, 26.9 mmol) inwater (140 mL) was added potassium hydroxide (85%; 3.55 g, 53.8 mmol)and the mixture was heated at reflux for 3.75 h, then allowed to cool toambient temperature. Hydrochloric acid (2.5N aqueous; 29 mL) was addedand the resultant precipitate was filtered and washed with water toafford a mixture [(2,3-g):(3,2-f) 1:1) of products (5.47 g, 100%) as anoff-white solid which was used without further purification.

7,8-Dihydrofuro[2, 3-g]indole and 5,6-dihydrofuro[3,2-f]indole

A stirred solution of 7,8-dihydrofuro[2,3-g]indole-2-carboxylic acid and5,6-dihydrofuro[3,2-f]indole-2-carboxylic acid (1:1) (5.46 g, 26.9 mmol)in phenyl ether (250 mL) was heated at reflux for 45 min, then allowedto cool to ambient temperature. Heptane (500 mL) was added and themixture was passed through a heptane-packed SiO₂ column under pressure.The column was eluted with heptane (1.5 L), then heptane-dichloromethane(1:1, 1L) and finally dichloromethane to afford7,8-dihydrofaro[2,3-g]indole (230 mg, 5.4% as a white solid. IR ν_(max)(Nujol)/cm⁻¹ 3382, 2925, 2854, 1644, 1618, 1497, 1463, 1441, 1435, 1368,1326, 1234, 1140, 1021, 970, 793, 719, 622, 533 and 475; NMR (400 MHz,CDCl₃) δ_(H) 3.31 (2H, t, J 8.5 Hz), 4.66 (2H, t, J 8.5 Hz), 6.51 (1H,dd, J 2, 3.5 Hz), 6.73 (1H, d, J8 Hz), 7.06 (1H, dd, J 2, 3.5 Hz), 7.39(1H, d, J 8.5 Hz) and 7.83 (1H, brs). Also collected were5,6-dihydrofuro[3,2-f]indole (667 mg, 15.6%) and mixed fractions (2.94g, 68.7%). The mixed isomers were further separated by flash columnchromatography [SiO₂; ethyl acetate-heptane (1:3)] to afford afford7,8-dihydrofuro[2,3-g]indole (408 mg, 9.5%) as a white solid and5,6-dihydrofuro[3,2-f]indole (690 mg, 16%).

(S)-1-[2-(tert-Butoxycarbonylamino)propyl]-7,8-dihydrofuro[2,3-g]indole

To a stirred solution of 7,8-dihydrofuro[2,3-g]indole (392 mg, 2.46mmol) in dimethyl sulfoxide under Ar at 38° C. (external temperature)was added powdered potassium hydroxide (85%; 650 mg, 9.85 mmol) and theresultant suspension was stirred for 1 h. A solution of(S)-2-(tert-butoxycarbonylamino)propane methanesulfonate (1.50 g, 5.9mmol) was added dropwise over 45 min, and the mixture was stirred for 4days. After this time, the reaction was quenched by pouring ontoice-water (100 mL), the resultant suspension was filtered and the solidwas washed with ice-cold water to afford the product (580 mg, 74%) as apale pink solid. R_(f) 0.25 [Ethyl acetate-heptane (3:7)]; IR ν_(max)(Nujol)/cm−1 3360, 2925, 2854, 1687, 1516, 1460, 1366, 1341, 1299, 1233,1224, 1173, 1079, 969, 794, 712 and 608; NMR (400 MHz, CDCl₃) δ_(H) 1.09(3H, d, J 6.5 Hz), 1.39 (9H, s), 3.52 (1H, m), 3.59 (1H, m), 3.99 (2H,m), 4.27 (1H, m), 4.63 (2H, t,J 9 Hz), 6.42 (1H, d,J3.5 Hz), 6.68 (J, d,J 8.5 Hz), 6.89 (1H, d, J3.5 Hz) and 7.33 (1H, d, J8.5 Hz).

(S)-1-[2-(tert-Butoxycarbonylamino)propyl]-2,3,7,8-tetrahydrofurol[2,3-g]indole

To a stirred solution/suspension of(S)-1-[2-(tert-butoxycarbonylamino)propyl]-7,8-dihydrofuro[2,3-g]indole(565 mg, 1.79 mmol) in acetic acid (40 mL) under Ar at 5° C. was addedsodium cyanoborohydride (371 mg, 5.90 mmol) and the mixture was allowedto warm to ambient temperature and stir overnight. The resultantsolution was poured onto ice-water (100 mL), basified (˜pH 8-9) by theaddition of 30% ammonium hydroxide, and the resultant suspension wasfiltered and the solid washed with ice-cold water. The crude solid waspurified by flash column chromatography [SiO₂; ethyl acetate-heptane(3:7)] to afford the product (412 mg, 72%) as a white solid: mp141-142.5° C.; Found: C, 67.87; H, 8.21; N, 8.80%. C₁₈H₂₆N₂O₃ requires:C, 67.90; H, 8.23; N, 8.79%.

(S)-1-(3,7,8-Tetrahydrofuro[2,3-g]indol-1-yl)-2-propylamine fumarate

To a stirred solution/suspension of(S)-1-[2-tert-butoxycarbonylamino)propyl]-2,3,7,8-tetrahydrofuro[2,3-g]indole (392 mg, 1.23 mmol) in methanol (25 mL) was added conc.hydrochloric acid (0.37 mL) and the mixture was heated at reflux for 1.5h, then allowed to cool to ambient temperature. The solvent was removedin vacuo and the residue was triturated with ether and a small amount ofacetone, filtered, and washed with ether to afford the product (366 mg,100%) as the bis-hydrochloride salt. 326 mg of this salt was partitionedbetween ether and aqueous sodium hydroxide solution, and the aqueousphase was extracted with ether. The combined organic fractions weredried (magnesium sulfate) and concentrated in vacuo to afford the freeamine as a pale yellow oil (216 mg). A solution of the above oil in hot2-propanol (0.5 mL) was added to a stirred solution of fumaric acid (127mg, 1.09 mmol) in hot 2-propanol (2 mL), and the resultant suspensionwas allowed to cool to ambient temperature and was then cooled to 0° C.The solid was filtered and washed with ice-cold 2-propanol, followed byether to afford the product (279 mg, 76%) as a white solid: mp.215.5-217° C. (dec.); Found: C, 60.98; H, 6.78; N, 8.26%.C₁₃H₁₈N₂O.C₄H₄O₄ requires: C, 61.07; H, 6.63; N, 8.37%.

Alternatively Example 3 may be synthesised using the followingprocedure.

2-(2′-Hydroxyethyl)-3-methoxy-N-tert-butoxycarbonyl-aniline

A stirred solution of N-tert-butoxycarbonyl-anisidine (431 g, 1.93 mol)in ether (2 L) under an argon atmosphere was cooled to −20° C. Asolution of tert-butyllithium (1.7 M, hexanes, 2.5 L, 4.25 mol) wasadded dropwise and the reaction was stirred for 3 h at −20° C. Thereaction was cooled to −50° C. and ethylene oxide (136 g, 3.09 mol) wasadded dropwise. The reaction was warmed to 0° C. over 1 h and thenstirred at room temperature for 1 h. The reaction was poured ontosaturated aqueous ammonium chloride solution (2.5 L) and the mixture wasextracted with ether (3×2.5 L). The organic extracts were combined andconcentrated in vacuo to afford a pale yellow oil which was purified bycolumn chromatography [SiO₂; heptane-ethyl acetate (5:1)] to afford thetitle compound (176 g, 37%) as a yellow crystalline solid; NMR (400MHz,CDCl₃) δ_(H) 1.51 (9H, br s), 2.91 (2H, t, J 6.0 Hz), 3.79 (3H, s), 3.87(2H, q, J 5.0 Hz, 10.5 Hz), 6.64 (1H, d, J 8.0 Hz), 7.18 (1H, t, J 9.0Hz), 7.38 (1H, m), 7.55 (1H, br s); IR ν_(max) (Nujol)/cm⁻¹ 3407, 3212,2955, 2854, 1721, 1592, 1508, 1476, 1438, 1370, 1267, 1234, 1162, 1047and 773.

3-Dihydro-4-benzofuranamine

2-(2′-Hydroxyethyl)3-methoxy-N-tert-butoxycarbonyl-aniline (158 g, 0.59mol) was added portionwise to a stirred solution of hydrogen bromide inacetic acid (30%, 1.7 L) at room temperature. The reaction was thenheated to reflux for 4 h. The reaction mixture was cooled to roomtemperature, basified to pH 14 with aqueous sodium hydroxide solution (6N) and extracted with dichloromethane (3×2 L). The organic extracts werecombined, dried (magnesium sulphate) and evaporated to give the titlecompound as an range oil (78 g, 92%); NMR (400MHz, CDCl₃) δ_(H) 2.99(2H, t, J 8.5 Hz), 3.55 (2H, br s), 4.57 (2H, t, J 8.5 Hz), 6.19 (1H, d,J 7.5 Hz), 6.25 (2H, d, J 7.5 Hz), 6.92 (1H, t, J 8.0 Hz); IR ν_(max)(Nujol)/cm⁻¹ 2853, 2610, 1544, 1462, 1262, 1234, 986 and 761.

N-[5-(2,3-Dihydrobenzo[b]furanyl)]-2-(hydroxyimino)acetamide

A mixture of 2,3-dihydro-4-benzofuranamine (72.3 g, 0.54 mol),hydroxylamine hydrochloride (131.3 g, 1.8 mol), conc. hydrochloric acid(45 mL) and water (1265 mL) was stirred at room temperature for 30 min.A solution of chloral hydrate (98.2 g, 0.59 mol) in water (1265 mL) wasadded followed by solid sodium sulphate (767 g, 5.4 mol) and thereaction was heated to reflux for 1 h. The reaction was cooled to roomtemperature and the solid was collected by filtration. The solid wassuspended in ethyl acetate (250 mL) and water (250 mL) and thenextracted with ethyl acetate (3×250 mL). The organic extracts werecombined, dried (magnesium sulphate) and concentrated in vacuo to affordthe title compound (41 g, 38%) as a pale brown solid; NMR (400MHz,DMSO-d₆) δ_(H) 3.12 (2H, t, J 9.0 Hz), 4.52 (2H, t, J 8.5 Hz), 6.58 (1H,d, J 8.0 Hz), 7.06 (1H, t, J 8.5 Hz), 7.14 (1H, d, J 8.5 Hz), 7.7 (1H,s), 9.66 (1H, br s), 12.19 (1H, br s); IR ν_(max) (Nujol)/cm⁻¹ 3389,3160, 2923, 1661, 1620, 1607, 1540, 1453, 1238, 1060, 1029, 982 and 780.

2,3,7,8-Tetrahydro-1H-furo[2,3-g]indole-2,3-dione

Methanesulfonic acid (200 mL) was added toN-[5-(2,3-dihydrobenzo[b]furanyl)]-2-(hydroxyimino)acetamide (17 g, 82.5mmol) with vigorous stirring at 0° C. The mixture was stirred at 0° C.for 1 h then poured onto ice-water (500 mL). The aqueous mixture wasneutralised (ammonium hydroxide) and filtered to afford the titlecompound (12.4 g, 80%) as a red solid; NMR (400 MHz, DMSO-d₆) δ_(H) 3.08(2H, t, J 8.5 Hz), 4.72 (2H, t, J 8.5 Hz), 6.45 (1H, d, J 8.0 Hz), 7.37(1H, d, J 8.0 Hz), 11.15 (1H, br s); IR ν_(max) (Nujol)/cm⁻¹ 3225, 2925,1752, 1709, 1642, 1605, 1490, 1448, 1377, 1357, 1243 and 1039.

7,8-Dihydro-1H-furo[2,3-g]indole

A solution of 2,3,7,8-tetrahydro-1H-furo[2,3-g]indole-2,3-dione (9.05 g,47.9 mmol) in tetrahydrofuran (100 mL) was stirred at −20° C. under anargon atmosphere. Solid sodium borohydride was added portionwise and thereaction was stirred for 20 min at −20° C. Boron trifluoride etherate(11.9 mL, 96 mmol) was added dropwise over 90 min, then the mixture waswarmed to 0° C. and stirred for 1 h. The reaction was quenched withwater (100 mL) and the solution was extracted with ethyl acetate (3×150mL). The organic extracts were combined, dried (magnesium sulphate) andconcentrated in vacuo to afford a yellow solid which was purified bycolumn chromatography [SiO₂; heptane-ethyl acetate (5:1)] to afford thetitle compound (3.2 g, 42.8%); analytical data as described above.

The synthesis of Example 3 was completed as described above.

Example 4

(S)-1-(2,3,7,8-Tetrahydro-9H-pyrano[2,3-g]indol-1-yl)-2-propylaminefumarate

To a stirred solution of 4-hydroxychroman (10.14 g, 67.5 mmol) in aceticacid (150 mL) under Ar was added acetic anhydride (12.7 mL, 135 mmol)and the mixture was heated at reflux for 3 h, then allowed to cool toambient temperature. Palladium on carbon (10 wt %; 1.8 g, 2.5 mol %) wasadded and the mixture was shaken in a Parr hydrogenator under a 42 psiatmosphere of hydrogen overnight. The reaction mixture was filtered, thesolvent was removed in vacuo and the residue was taken-up in ethylacetate. The solution was washed with saturated aqueous sodiumbicarbonate solution, brine, dried (magnesium sulfate) and concentratedin vacuo to afford the product (7.73 g, 85%) as a pale yellow liquid: IRν_(max) (film)/cm⁻¹ 2937, 2863, 1737, 1609, 1582, 1490, 1456, 1304,1267, 1228, 1189, 1116, 1065, 1008 and 754; NMR (400 MHz, CDCl₃) δ_(H)2.00 (2H, m), 2.78 (2H, t, J 6.5 Hz), 4.17 (2H, t, J 7 Hz), 6.81 (2H, m)and 7.05 (2H, m).

Chroman-6-carboxaldehyde and chroman-8-carboxaldehyde

A mixture of chroman-6-carboxaldehyde and chroman-8-carboxaldehyde wasprepared according to the method described in Example 3, using chroman(7.70 g, 57.4 mmol) to produce a mixture [6-CHO:8-CHO (1:1)] of aldehydeproducts (8.98 g, 96%) as a pale orange liquid which was used withoutfurther purification.

Methyl 2-azido-3-(2,3-dihydro-4H-benzopyran-6-yl)propenate and methyl2-azido-3-(2,3-dihydro-4H-benzopyran-8-yl)propenate

Methyl 2-azido-3-(2,3-dihydro4H-benzopyran-6-yl)propenate and methyl2-azido-3-(2,3-dihydro4H-benzopyran-8-yl)propenate were preparedaccording to the method described in Example 3, using a mixture (1:1) ofchroman-6-carboxaldehyde and chroman-8-carboxaldehyde (8.95 g, 55.2mmol) to produce after purification by flash column chromatography[SiO₂; dichloromethane-heptane (1:1)] a mixture[6-substituted:8-substituted (3:1)] of products (5.15 g, 36%) as a paleyellow solid which was used without further purification.

Methyl 7,8-dihydro-9H-pyrano[2,3-g]indole-2-carboxylate, methyl6,7-dihydro-5H-pyrano[3,2-f]indole-2-carboxylate and methyl5,6-dihydro-7H-pyrano[2,3-e]indole-2-carboxylate

Methyl 7,8-dihydro-9H-pyrano[2,3-g]indole-2-carboxylate, methyl6,7-dihydro-5H-pyrano[3,2-f]indole-2-carboxylate and methyl5,6-dihydro-7H-pyrano[2,3-e]indole-2-carboxylate were prepared accordingto the method described in Example 3, using a mixture (3:1) of methyl2-azido-3-(2,3-dihydro-4H-benzopyran-6-yl)propenate and methyl2-azido-3-(2,3-dihydro4H-benzofuran-8-yl)propenate (5.1 g, 19.7 mmol) toproduce a mixture [(2,3-g):(3,2-f):(2,3-e)-10:2:5] of products (4.33 g,94%) as a yellow solid which was used without further purification.

7,8-Dihydro-9H-pyrano[2,3-g]indole-2-carboxylic acid,6,7-dihydro-5H-pyrano[3,2-f]indole-2-carboxylic acid and5,6-dihydro-7H-pyrano[2,3-e]indole-2-carboxylic acid

7,8-Dihydro-9H-pyrano[2,3-g]indole-2-carboxylic acid,6,7-dihydro-5H-pyrano [3,2-f]indole-2-carboxylic acid and5,6-dihydro-7H-pyrano[2,3-e]indole-2-carboxylic acid were preparedaccording to the method described in Example 3, using a mixture (10:5:2)of methyl 7,8-dihydro-9H-pyrano[2,3-g]indole-2-carboxylate, methyl6,7-dihydro-5H-pyrano[3,2-f]indole-2-carboxylate and methyl5,6-dihydro-7H-pyrano[2,3-e]indole-2-carboxylate (4.33 g, 18.7 mmol) toproduce, after trituration with isopropyl ether, a mixture[(2,3-g):(3,2-f):(2,3-e)-7:1:2] of products (2.30 g, 57%) as a whitesolid. The filtrate was evaporated and purified by flash columnchromatography [SiO₂; ethyl acetate-heptane (2:1)+0.5% acetic acid] toafford an oil which solidified upon treatment with isopropylether-heptane to afford a mixture [(2.3-g):(3,2-f):(2,3-e)-44:22:34] ofproducts (818 mg, 20%) as a white solid. The products were combined andused without further purification.

7,8-Dihydro-9H-pyrano[2,3-g]indole, 6,7-dihydro-5H-pyrano[3,2-g]indoleand 5,6-dihydro-7H-pyrano[2,3-e]indole

7,8-Dihydro-9H-pyrano[2,3-g]indole, 6,7-dihydro-5H-pyrano[3,2-g]indoleand 5,6-dihydro-7H-pyrano[2,3-e]indole were prepared according to theprocedure described in Example 3, using a mixture[(2,3-g):(3,2-f):(2,3-e)-11:1:4] of7,8-dihydro-9H-pyrano[2,3-g]indole-2-carboxylic acid,6,7-dihydro-5H-pyrano[3,2-f]indole-2-carboxylic acid and5,6-dihydro-7H-pyrano[2,3-e]indole-2-carboxylic acid (3.12 g, 14.4 mmol)to produce, after flash column chromatography (and without furtherseparation on a second column) a mixture [(2,3-g):(2,3-e)-72:28] ofproducts (2.01 g, 80%) as a white, crystalline solid [R_(f) 0.46 (SiO₂;dichloromethane)] which was used without further purification. Alsocollected was 6,7-dihydro-5H-pyrano[3,2-f]indole (250 mg, 10%) as anoff-white solid [R_(f) 0.33 (SiO₂; dichloromethane)].

(S)-1-[2-(tert-Butoxycarbonylamino)propyl]-7,8-dihydro-9H-pyrano[2,3-g]indole

(S)1-[2-(tert-Butoxycarbonylamino)propyl]-7,8-dihydro-9H-pyrano[2,3-g]indolewas prepared according to the method described in Example 3, using amixture [(2,3-g):(2,3-e)-7:3] of 7,8-dihydro-9H-pyrano[2,3-g]indole and5,6-dihydro-7H-pyrano[2,3-e]indole (1.34 g, 7.7 mmol) to produce, afterpurification by flash column chromatography [SiO₂; ethyl acetate-heptane(1:4)], the product (890 mg, 35%) as a white solid: IR ν_(max)(Nujol)/cm⁻¹ 3352, 2925, 2855, 1687, 1611, 1528, 1458, 1424, 1367, 1358,1247, 1167, 1054, 961, 704 and 632; NMR (400 MHz, CDCl₃) δ_(H) 1.03 (3H,d, J 7 Hz), 1.36 (9H, s), 3.10 (1H, m), 3.18 (1H, m), 3.94 (1H, sept, J7 Hz), 4.12 (1H, m), 4.15 (2H, dd, J 4.5, 6 Hz), 4.46 (1H, m), 6.35 (1H,d, J 3 Hz), 6.63 (1H, d, J 8.5 Hz), 6.82 (1H, d, J 3 Hz) and 7.27 (1H,d, J 8.5 Hz).

(S)-1-[2-(tert-Butoxycarbonylamino)propyl-2,3,7,8-tetrahydro-9H-pyrano[2,3-g]indole

(S)-1-[2-(tert-Butoxycarbonylamino)propyl]-2,3,7,8-tetrahydro-9H-pyrano[2,3-g]indolewas prepared according to the procedure described in Example 3, using(S)-1-[2-(tert-butoxycarbonylamino)propyl]-7,8-dihydro-9H-pyrano[2,3-g]indole(870 mg, 2.63 mmol) with the following modification. After thebasification step, the mixture was extracted with chloroform, washedwith brine, dried (magnesium sulfate) and concentrated in vacuo toafford the product (860 mg, 98%) as a white solid: mp. 137-140° C.;Found: C, 68.71; H, 8.49; N, 8.39%. C₁₉H₂₈N₂O₃ requires: C, 68.65; H,8.49; N, 8.42%.

(S)-1-(2,3,7,8-Tetrahydro-9H-pyrano[2,3-g]indol-1-yl)-2-propylaminefumarate

(S)1-(2,3,7,8-Tetrahydro-9H-pyrano[2,3-g]indol-1-yl)-2-propylaminefumarate was prepared according to the method described in Example 3,using(S)-1-[2-(tert-butoxycarbonylamino)propyl]-2,3,7,8-tetrahydro-9H-pyrano[2,3-g]indole(820 mg, 2.47 mmol) with the following modification. After evaporationof the methanol, the residue was partitioned between ether and aqueoussodium hydroxide (2N), the aqueous phase was extracted with ether, dried(magnesium sulfate) and concentrated in vacuo to afford the free amineas a pale yellow oil (572 mg, 100%). The fumarate was formed accordingto the procedure described in Example 3, giving the product (728 mg,79%) as a white solid: mp. 168-169° C.; Found: C, 62.02; H, 7.14; N,8.02%. C₁₄H₂₀N₂O.C₄H₄O₄ requires: C, 62.05; H, 6.94; N, 8.04%.

Example 5

(S)1-(2,3,7,8-Tetrahydrothieno[2,3-g]indol-1-yl)-2-propylamine fumarate

2,3-Dihydrobenzo[b]thiophene, 1,1-dioxide

To a stirred solution/suspension of benzo[b]thiophene, 1,1-dioxide (25.0g, 0.15 mol) in a mixture of tetrahydrofuran (165 mL) and ethanol (110mL) under Ar at ambient temperature was added palladium on carbon (10 wt%; 880 mg) and the mixture was shaken under a 20 psi hydrogen atmospherefor 15 min. The reaction mixture was filtered and concentrated in vacuoto afford the product (24.68 g, 98%) as a yellow oil: IR ν_(max)(Nujol)/cm⁻¹ 2925, 2854, 1600, 1456, 1378, 1292, 1266, 1196, 1148, 1120,1060, 982, 854, 787, 746, 600, 549 and 516; NMR (400 MHz, CDCl₃) δ_(H)3.35 (2H, t, J 6.5 Hz), 3.68 (2H, t, J 6.5 Hz), 7.52 (1H, m), 7.55 (1H,m), 7.66 (1H, dt, J 7.5, 1 Hz), 7.74 (1H, d, J 7.5 Hz).

2,3-Dihydrobenzo[b]thiophene

To a stirred solution of 2,3-dihydrobenzo[b]thiophene, 1,1-dioxide(24.62 g, 146 mmol) in tetrahydrofuran (350 mL) under Ar at ambienttemperature was added a solution of lithium aluminium hydride (1.0 M intetrahydrofuran; 161 mL, 161 mmol) dropwise over 10 min, then themixture was heated at reflux for 30 min. The reaction was allowed tocool to ambient temperature, then quenched by the dropwise addition ofwater (6.6 mL) followed by 15% aqueous sodium hydroxide (6.6 mL), thenwater (19.9 mL). The mixture was filtered, diluted with ether, washedwith brine, dried (magnesium sulfate) and concentrated in vacuo toafford the crude product. Purification by flash column chromatography(SiO₂; heptane) afforded the product (4.80 g, 24%) as a pale yellow oil:R_(f) 0.35 (heptane); NMR (400 MHz, CDCl₃) δH 3.27 (1H, m), 3.28 (1H, d,J 7 Hz), 3.33 (1H, d, J 7 Hz), 3.35 (1H, dd, J 2.5, 4 Hz), 7.00 (1H, dt,J 1.5, 6 Hz), 7.10 (1H, dt, J 1.5, 6 Hz), 7.18 (1H, d, J 7.5 Hz), 7.21(1H, d,J 7.5 Hz).

2,3-Dihydrobenzo[b]thiophene-5-carboxaldehyde and2,3-Dihydrobenzo[b]thiophene-7-carboxaldehyde

A mixture of 2,3-dihydrobenzo[b]thiophene-5-carboxaldehyde and2,3-dihydrobenzo[b]thiophene-7-carboxaldehyde was prepared according tothe method described in Example 3, using 2,3-dihydrobenzo[b]thiophene(4.8 g, 35.2 mmol) to produce, after purification by flash columnchromatography [SiO₂; heptane-ether (4:1→2:1)] a mixture [5-CHO:7-CHO(1.3:1)] of aldehyde products (2.55 g, 44%) as a yellow oil which wasused without further purification.

Methyl 2-azido-3-(2,3-dihydrobenzo[b]thiophene-5-yl)propenate and methyl2-azido-3-(2,3-dihydrobenzo[b]thiophene-7-yl)propenate

Methyl 2-azido-3-(2,3-dihydrobenzo[b]thiophene-5-yl)propenate and methyl2-azido-3-(2,3-dihydrobenzo[b]thiophene-7-yl)propenate were preparedaccording to the method described in Example 3, using the above mixture(1.3:1) of 2,3-dihydrobenzo[b]thiophene carboxaldehydes and (2.55 g,15.53 mmol) to produce (without purification by flash columnchromatography) a mixture [5-substituted:7-substituted (1.4:1)] ofproducts (3.61 g, 89%) as a pale yellow oil which was used withoutfurther purification.

Methyl 7,8-dihydrothieno[2,3-g]indole-2-carboxylate, methyl5,6-dihydrothieno[3,2-f]indole-2-carboxylate and methyl5,6-dihydrothieno[2,3-e]indole-2-carboxylate

Methyl 7,8-dihydrothieno[2,3-g]indole-2-carboxylate, methyl5,6-dihydrothieno[3,2-f]indole-2-carboxylate and methyl5,6-dihydrothieno[2,3-e]indole-2-carboxylate were prepared according tothe method described in Example 3, using a mixture (1.4:1) of the above2-azidopropenates (3.61 g, 13.8 mmol), with the following modification.The addition of the substrate to the refluxing xylenes was carried outover 2.5 h, heated for a further 0.5 h, then allowed to cool to ambienttemperature. The solvent was removed in vacuo and the crude product waspurified by flash column chromatography (SiO₂; dichloromethane) toafford a mixture [(2,3-g):(3,2-f):(2,3-e)-34:44:22] of products (1.92 g,60%) as a white solid which was used without further purification.

7,8-dihydrothieno[2,3-g]indole-2-carboxylic acid,5,6-dihydrothieno[3,2-f]indole-2-carboxylic acid and5,6-dihydrothieno[2,3-e]indole-2-carboxylic acid

7,8-dihydrothieno[2,3-g]indole-2-carboxylic acid,5,6-dihydrothieno[3,2-f]indole-2-carboxylic acid and5,6-dihydrothieno[(2,3-e]indole-2-carboxylic acid were preparedaccording to the method described in Example 3, using a mixture(34:44:22) of the above methyl dihydrothienoindole-2-carboxylates (1.84g, 7.89 mmol) to produce a mixture [(2,3-g):(3,2-f):(2,3-e)-41:35:24] ofproducts (1.65 g, 95%) as a pale green solid which was used withoutfurther purification.

7,8-Dihydrothieno[2,3-g]indole, 5,6-dihydrothieno[3,2-f] and5,6-dihydrothieno[2,3-e]indole

7,8-Dihydrothieno[2,3-g]indole, 5,6-dihydrothieno[3,2-f] and5,6-dihydrothieno[2,3-e]indole were prepared according to the methoddescribed in Example 3, using the above mixture ofdihydrothienoindole-2-carboxylic acids (1.64 g, 7.48 mmol), with thefollowing modification. After the mixture had been passed down theheptane-packed column and the phenyl ether flushed-off with heptane, theeluant was increased to heptane-dichloromethane (1:1→1:3) to afford apurple solid. The solid was recrystallised [heptane-isopropyl ether(1:1)] to afford a mixture (2:3) of 7,8-dihydrothieno[2,3-g]indole and5,6-dihydrothieno[3,2-f]indole (540 mg, 41%) as a pink solid. Thefiltrate was evaporated to afford a mixture (25:30:45) of7,8-dihydrothieno[2,3-g]indole, 5,6-dihydrothieno[3,2-f]indole and5,6-dihydrothieno[2,3-e]indole (644 mg, 49%) as a purple solid which wasused without further purification.

(S)-1-[2-(tert-Butoxycarbonylamino)propyl]-7,8-dihydrothieno[2,3-g]indole

(S)-1-[2-(tert-Butoxycarbonylamino)propyl]-7,8-dihydrothieno[2,3-g]indolewas prepared according to the method described in Example 3, using amixture (25:30:45) of 7,8-dihydrothieno[2,3-g]indole,5,6-dihydrothieno[3,2-f]indole and 5,6-dihydrothieno[2,3-e]indole (617mg, 3.52 mmol) to afford, after purification by flash columnchromatography [SiO₂; ethyl acetate-heptane (1:3)], the product (200 mg,17%) as a white solid: IR ν_(max) (Nujol)/cm⁻¹ 3347, 2922, 2855, 1680,1520, 1460, 1378, 1364, 1314, 1252, 1169, 1056, 884, 798 and 721; NMR(400 MHz, CDCl₃) δ_(H) 1.08 (3H, d, J 7 Hz), 1.40 (9H, s), 3.45 (2H, dt,J, 1.5, 6 Hz), 3.61 (1H, m), 3.72 (1H, m), 3.98 (1H, m), 4.08 (1H, m),4.39 (2H, m),6.42(1H, d, J 3 Hz), 6.90(1H, d, J 3Hz), 6.98 (1H, d,J 8Hz), 7.38(lH, d,J 8 Hz).

(S)-1-[2-(tert-Butoxycarbonylamino)propyl]-2,3,7,8-tetrahydrothieno[2,3-g]indole

(S)-1-[2-tert-Butoxycarbonylamino)propyl]-2,3,7,8-tetrahydrothieno[2,3-g]indolewas prepared according to the method described in Example 3, using(S)-1-[2-(tert-butoxycarbonylamino)propyl]-7,8-dihydrothieno[2,3-g]indole(200 mg, 0.60 mmol) to produce, after purification by flash columnchromatography [SiO₂; ethyl acetate-heptane (1:4)], the product (138 mg,69%) as a pale green solid: mp. 170-171.5 ° C.; Found: C, 64.60; H,7.72; N, 8.37%. C₁₈H₂₆N₂O₂S requires: C, 64.64; H, 7.83; N, 8.37%.

(S)-1-(2,3,7,8-Tetrahydrothieno[2,3-g]indol-1-yl)-2-propylamine fumarate

(S)-1-(2,3,7,8-Tetrahydrothieno[2,3-g]indol-1-yl)-2-propylamine fumaratewas prepared according to the method described in Example 3, using(S)-1-[2-(tert-butoxycarbonylamino)propyl]-2,3,7,8-tetrahydrothieno[2,3-g]indole(122 mg, 0.36 mmol) to produce the product (104 mg, 82%) as a whitesolid: mp. 188-189.5° C. (dec.); Found: C, 57.98; H, 6.33; N, 7.90%.C₁₃H₁₈N₂S.C₄H₄O₄ requires: C, 58.27; H, 6.33; N, 7.99%.

Example 6

(S)-1-(2,3,7,8-Tetrahydro-9H-1,4-dioxino[2,3-g]indol-9-yl)-2-propylaminefumarate

Methyl 2-azido-3-(1,4-benzodioxan-6-yl)propenate

Methyl 2-azido-3-(1,4-benzodioxan-6-yl)propenate was prepared accordingto the method described in Example 3, using1,2-benzodioxan-6-carboxaldehyde (4.67 g, 28.5 mmol) to produce theproduct (3.89 g, 52%) as a pale yellow solid: JR ν_(max) (Nujol)/cm⁻¹2925, 2854, 2121, 1710, 1699, 1620, 1608, 1601, 1576, 1508, 1466, 1434,1381, 1317, 1300, 1265, 1252, 1236, 1211, 1165, 1157, 1125, 1084, 1066,1050, 967, 952, 920, 906, 888, 862, 840, 805, 774, 756, 725, 663, 616and 563; NMR δ_(H) (400 MHz; CDCl₃) 3.39 (1H, s), 4.25-4.31 (4H, m),6.81 (1H, s), 6.86 (1H, d,J 8.5 Hz),7.24(1H, dd,J 8.5, 2.0Hz) and 7.51(1H, d, J 2.0 Hz).

Methyl 2, 3-dihydro-9H-1, 4-dioxino[2,3-g]indole-8carboxylate

Methyl 2,3-dihydro-9H-1,4-dioxino[2,3-g]indole-8-carboxylate wasprepared according to the procedure described in Example 3, using methyl2-azido-3-1,4-benzodioxan-6-yl)propenate (3.81 g, 14.58 mmol), with thefollowing modification. The addition of the substrate to the refluxingxylenes was carried out over 5 h, the mixture was heated for a further0.5 h, then the solvent was removed in vacuo. The resultant crudeproduct was purified by flash column chromatography (SiO₂;dichloromethane) to afford the product (1.58 g, 46%) as a white solid:IR ν_(max) (Nujol)/cm⁻¹ 3302, 2927, 2855, 1748, 1712, 1694, 1634, 1589,1548, 1513, 1455, 1392, 1377, 1320, 1277, 1257, 1200, 1102, 1084, 1019,990, 935, 910, 875, 835, 824, 802, 788, 773, 748, 742, 685, 634, 596,583, 562, 546, 534, 486 and 458; NMR δ_(H) (400 MHz; CDCl₃) 3.92 (1H,s), 4.32-4.39 (4H, m), 6.75 (1H, d, J 8.5 Hz), 7.11-7.15 (2H, m) and8.90 (1H, br s).

2,3-Dihydro9H-1,4-dioxino[2,3-g]indole-8-carboxylic acid

2,3-Dihydro-9H-1,4-dioxino[2,3-g]indole-8-carboxylic acid was preparedaccording to the method described in Example 3, using methyl2,3-dihydro-9H-1,4-dioxino[2,3-g]indole-8-carboxylate (1.61 g, 6.90mmol) to produce, after recrystallisation [ethanol-water (1:2)], theproduct (1.25 g, 82%) as a pale pink crystalline solid: mp 222-223° C.(dec.); Found: C, 60.06; H, 4.11; N, 6.33%. C₁₁H₉NO₄ requires: C, 60.28;H. 4.14; N, 6.39%.

2,3-Dihydro-9H-1,4-dioxino[2,3-g]indole

2,3-Dihydro-9H-1,4-dioxino[2,3-g]indole was produced according to themethod described in Example 3, using 2,3dihydro-9H-1,4-dioxino[2,3-g]indole-8-carboxylic acid (1.192 g, 5.44mmol) to produce the product (934 mg, 98%) as a pale yellow oil: NMRδ_(H) (400 MHz; CDCl₃) 4.27-4.37 (4H, m), 6.65 (1H, d, J 8.5 Hz), 7.01(1H, d, J 2.0 Hz), 7.07 (1H, d, J 8.5 Hz), 11.52 (1H, s) and 12.65 (1H,br s); Found: C, 68.56; H, 5.12; N, 7.75%. C₁₀H₉NO₂ requires: C, 68.56;H, 5.18; N, 7.99%.

(S)-9-[2-(tert-Butoxycarbonylamino)propyl]-(2,3-dihydro-9H-1,4-dioxino[2,3-g]indole

(S)-9-[2-tert-Butoxycarbonylamino)propyl]-(2,3-dihydro-9H-1,4-dioxino[2,3-g]indole was prepared according to theprocedure described in Example 3, using2,3-dihydro-9H-1,4-dioxino[2,3-g]indole (875 mg, 4.99 mmol) to produce,after purification by flash column chromatography [SiO₂; ethylacetate-heptane (1:4→3:7)], the product (1.113 g, 67%) as a white solid:IR ν_(max) (Nujol)/cm⁻¹ 3420, 3104, 2926, 2825, 1705, 1627, 1583, 1506,1460, 1434, 1376, 1367, 1352, 1322, 1272, 1257, 1205, 1178, 1160, 1090,1059, 966, 878, 795, 714, 632 and 492; NMR (400 MHz, CDCl₃) δ_(H) 1.11(3H, d, J 6.5 Hz), 1.28 (9H, s), 4.00 (1H, sept, J 7 Hz), 4.21 (1H, m),4.30 (2H, dt, J 1,3.5 Hz), 4.36 (2H, dt, J 3.5, 1 Hz), 4.74 (1H, m),6.35 (1H, d, J 3 Hz), 6.65 (1H, d, J 8.5 Hz), 6.86 (1H, d, J 3 Hz), 7.01(1H, d, J 8.5 Hz).

(S)-9-[2-(tert-Butoxycarbonylamino)propyl]-2,3,7,8-tetrahydro-9H-1,4-dioxino[2,3-g]indole

(S-9-[2-(tert-Butoxycarbonylamino)propyl]-2,3,7,8-tetrahydro-9H-1,4-dioxino[2,3-g]indolewas prepared according to the procedure described in Example 3, using(S)-9-[2-(tert-butoxycarbonylamino)propyl]-(2,3-dihydro-9H-1,4-dioxino[2,3-g]indole (1.09 g, 3.28 mmol) to produce, afterpurification by flash column chromatography [SiO₂; ethyl acetate-heptane(1:4)], the product (896 mg, 81%) as a white solid: mp 129.5-132° C.;Found: C, 64.61; H, 7.87; N, 8.32%. C₁₈H₂₆N₂O₄ requires: C, 64.65; H,7.84; N, 8.37%

(S)-1-(2,3,7,8-Tetrahydro-9H-1,4-dioxino[2,3-g]indol-9-yl)-2-propylaminefumarate

(S)-1-(2,3,7,8-Tetrahydro-9H-1,4-dioxino[2,3-g]indol-9-yl)-2-propylaminefumarate was prepared according to the procedure described in Example 3,using(S)-9-[2-(tert-butoxycarbonylamino)propyl]-2,3,7,8-tetrahydro-9H-1,4-dioxino[2,3-g]indole(870 mg, 2.60 mmol) to produce the product (723 mg, 79%) as a whitesolid: mp 173-174° C. (dec.); Found: C, 58.09; H, 6.36; N, 7.95%.C₁₃H₁₈N₂O₂.C₄H₄O₄ requires: C, 58.28; H, 6.33; N, 7.99%

Example 7

(S)-1-(2,3,6,7,8,9-Hexahydro-1H-benz[g]indol-1-yl)]-2-propylamine,fumarate

6,7,8,9-Tetrahydro-1H-benz[g]indole-2,3-dione

The benz[g]isatin was prepared in two steps from5,6,7,8-tetrahydro-1-naphthylamine using the methods described for1,6,7,8-tetrahydrocyclopenta[g]indole-2,3-dione (G. W. Rewcastle et.al., J. Med. Chem., 1991, 34, 217). The product (54% yield fromN-[1-(5,6,7,8-tetrahydronaphthalenyl)]-2-(hydroximino)acetamide) wasobtained as an orange solid: mp. 234-235° C. (lit. [U.S. Pat. No.1,856,210, 1929] 232° C.); NMR δ_(H) (400MHz; DMSO-d₆) 1.73 (4H, m),2.49 (2H, m), 2.73 (2H, m), 6.78 (1H, d, J 7.7 Hz), 7.21 (1H, d, J 7.7Hz) and 10.92 (1H, s).

6,7,8,9-Tetrahydro-]H-benz[g]indole

To a suspension of lithium aluminium hydride (2.85 g, 75.0 mmol) in drytetrahydrofuran (150 mL) was added6,7,8,9-tetrahydro-1H-benz[g]indole-2,3-dione (3.018 g, 15.0 mmol)portionwise over 30 min. The green suspension was heated under refluxfor 18 h and then cooled to 0° C. The suspension was treated with water(2.8 mL), 5 N aqueous sodium hydroxide (2.1 mL), and water (9.2 mL), andwas stirred for an additional 1 h. The suspension was then filtered, theresidue was washed with tetrahydrofuran and the filtrate thenconcentrated in vacuo. The residue obtained was purified by columnchromatography [SiO₂; ethyl acetate-heptane (1:19)] and triturated withhexane to give the title indole (1.58 g, 62%) as a white solid: mp.93-94° C. (lit. [Khim. Geterotsikl. Soedin., 1978, 14, 634) 89-90° C.;Found: C, 84.25; H, 7.65; N, 8.16%. C₁₂H₁₃N requires C, 84.17; H, 7.65;N, 8.18%.

(S)-1-[2-(tert-Butoxycarbonylamino)]-6,7,8,9-tetrahydro-]H-benz[g]indole

To a suspension of powdered potassium hydroxide (85%; 2.11 g, 32.0 mmol)in methyl sulfoxide (30 mL) at 40° C. was added6,7,8,9-tetrahydro-1-benz[g]indole (1.37 g, 8.0 mmol). The greensuspension was stirred at 40° C. for 1 h, and then a solution of(S)-2-(tert-butoxycarbonylamino)propane methanesulfonate (5.07 g, 20.0mmol) in methyl sulfoxide (10 mL) was added dropwise over 1 h. Thesuspension was heated at 40° C. for 66 h, poured onto a mixture of ice(150 g) and water (50 mL) and extracted with isopropyl ether (2×50 mL).The combined organic extracts were washed with water (50 mL), dried(sodium sulfate) and concentrated in vacuo. The residue obtained waspurified by column chromatography [SiO₂; ethyl acetate-heptane (1:1)]and triturated with hexane to give the title carbamate (1.49 g, 57%), asa white solid: mp. 118-119° C.; Found: C, 72.65; H, 8.75; N, 8.45%.C₂₀H₂₈N₂O₂ requires C, 73.14; H, 8.59; N, 8.52%; NMR δ_(H) (400 MHz;CDCl3) 7.34 (1 H, d, J 8.0 Hz), 6.92 (1 H, m), 6.82 (1 H, d, J 8.0 Hz),6.40 (1 H, m), 4.4 (1 H, br), 4.28 (1 H, m, J 6.5 Hz), 3.96 (1 H, m, J6.8 Hz), 3.16 (2 H, m), 2.91 (2 H, m), 1.89 (2 H, m), 1.83 (2 H, m),1.45 (9 H, br s) and 1.07 (3 H, d, J 6.8 Hz).

(S)-1-[2-(tert-Butoxycarbonylamino)]-2,3,6,7,8,9-hexahydro-]H-benz[g]indole

To a solution of(S)-1-[2-(tert-butoxycarbonylamino)]-6,7,8,9-tetrahydro-1H-benz[g]indole(0.985 g, 3.0 mmol) in acetic acid (50 mL) cooled in ice was addedsodium cyanoborohydride (0.60 g, 9.55 mmol) in one portion. The solutionwas stirred for 18 h and was poured onto a mixture of ice (150 g) andwater (50 mL). The suspension was stirred for 15 min and more ice wasadded. The suspension was basified with ammonium hydroxide (140 mL) andextracted with ethyl acetate (2×100 mL). The combined organic extractswere washed with water (100 mL), dried (magnesium sulfate) andconcentrated in vacuo. The residue obtained was purified by columnchromatography [SiO₂; ethyl acetate:heptane (1:4)] to give the titlecarbamate (0.935 g, 94%) as a pale purple solid: mp. 91-91.5° C.; Found:C, 72.7; H, 9.2; N, 8.4%. C₂₀H₃₀N₂O₂ requires C, 72.7; H, 9.15; N, 8.5%;NMR (400 MHz, CDCl₃) δ_(H) 6.90 (1 H, d, J 7.5 Hz), 6.58 (1 H, d, J 7.5Hz), 4.69 (1 H, br s), 3.84 (1 H, m), 3.42 (2 H, m), 3.14 (1 H, m), 2.99(3 H, m), 2.77 (2 H, m), 2.66 (2 H, m), 1.75 (4 H, m), 1.44 (9 H, s) and1.26 (3 H, d, J 6.6 Hz).

(S)-1-(2,3,6,7,8,9-Hexahydro-1H-benz[g]indol-1-yl)]-2-propylaminefumarate

To a stirred solution of(S)-1-[2-(tert-butoxycarbonylamino)]-2,3,6,7,8,9-hexahydro-1H-benz[g]indole(0.859 g, 2.60 mmol) in methanol (8.6 mL) was added hydrogen chloride (4M in dioxan; 6.5 mL, 26 mmol). The solution was stirred for 3 h and wasconcentrated in vacuo. The oil was partitioned between dichloromethane(25 mL) and 0.5 N aqueous sodium hydroxide (25 mL), and the aqueousphase was extracted with dichloromethane (25 mL). The combined organicphases were washed with water (25 mL), dried (sodium sulfate) andconcentrated in vacuo to give an oil which was dissolved in 2-propanol(7 mL) at 40° C. The solution was added dropwise to a solution offumaric acid (0.377 g, 3.25 mmol) in 2-propanol (7 mL) at 0° C. Thewhite suspension was cooled to 0° C. and filtered. The filter-cake waswashed with 2-propanol and ether and dried to give the title compound(0.789 g, 79%) as a white solid: mp. 178-182° C.; Found: C, 65.6; H,7.6; N, 8.05%. C₁₅H₂₂N₂.C₄H₄O₄ requires C, 65.9; H, 7.6; N, 8.1%; NMR(400 MHz; DMSO-d₆) δ_(H) 6.84 (1 H, d, J 7.5 Hz), 6.52 (1 H, d, J 7.5Hz), 6.44 (2 H, s), 3.37 (2 H, m), 3.23 (2 H, m), 3.00 (1 H, m), 2.89 (2H, m), 2.64 (4 H, m), 1.65 (4 H, m) and 1.26 (3 H, d, J 6.5 Hz).

Example 8

(S)-1-[1-(1,2,3,6,7,8-Hexahydrocyclopent[g]indolyl)]-2-propylaminefumarate

4-Aminoindan fumarate

4-Aminoindan fumarate was prepared according to the methods described inJ. Chem. Soc., Perkin Trans. 1, 1975, 519-23.

Cyclopent[g]isatin

Cyclopent[g]isatin was prepared according to the methods described in J.Med. Chem., 1991, 34(1), 217-222. Yield: 5.25 g, 69%, m.p.>330° C.; NMR(400 MHz; DMSO-d₆) δ_(H) 11.11 (1H, s), 7.30 (1H, d, J 7.6), 6.94 (1H,d, J 7.6), 2.88 (2H, t, J 7.5), 2.75 (2H, t, J 7.4), 2.06 (2H, m, J 7.4and 7.5).

1,6,7,8- Tetrahydrocyclopent[g]indole

A mixture of cyclopent[g]isatin (4.68 g, 25 mmol) and lithium aluminiumhydride (4.78 g, 5 equiv) in anhydrous tetrahydrofuran (250 mL) under anargon atmosphere was heated under reflux for 18 h. The mixture wascooled to 0° C. and water (5 mL) then aqueous sodium hydroxide solution(4 mL) followed by water (16 mL) were added sequentially dropwise. Themixture was stirred for 1 h then filtered, washing with tetrahydrofuran(100 mL). To the filtrate was added silica (25 g). The suspension wasconcentrated in vacuo and purified by column chromatography [SiO₂;heptane-ethyl acetate (19:1)] to give the product as an off-white solid(1.64 g, 42%); m.p. 79-81° C. (hexane); Found: C, 83.99; H, 7.05; N,8.93%. C₁₁H₁₁N requires: C, 84.04; H, 7.05; N, 8.91%.

(S)-tert-Butyl-[2-[1-[1-(1,6,7,8-tetrahydrocyclopent[g]indolyl)]propyl]carbamate

(S)-tert-Butyl-[2-[1-[1-(1,6,7,8-tetrahydrocyclopent[g]indolyl)]]propyl]carbamatewas prepared from 1,6,7,8-tetrahydrocyclopent[g]indole using the methodsdescribed above for Example 1 (2.1 g, 66%); m.p. 115-116° C. (hexane);Found: C, 72.59; H, 8.43; N, 8.91%. C₁₉H₂₆N₂O₂ requires: C, 72.58; H.8.33; N, 8.91%.

(S)-tert-Butyl-[2-[1-[1-(1,2,3,6,7,8-hexahydrocyclopent[g]indolyl)]]propyl]carbamate

(S)-tert-Butyl-[2-[1-[1-(1,2,3,6,7,8-hexahydrocyclopent[g]indolyl)]]propyl]carbamatewas prepared from(S)-tert-butyl-[2-[1-[1-(1,6,7,8-tetrahydrocyclopent[g]indolyl)]]propyl]carbamateusing the method described above for Example 1 (1.36 g, 86%); m.p. 124°C. (hexane); Found: C, 72.05; H, 8.97; N, 8.82%. C₁₉H₂₈N₂O₂ requires C,72.12; H, 8.92; N, 8.85%.

(S)-1-[1-(1,2,3,6,7,8-Hexahydrocyclopent[g]indolyl)]-2-propylaminefumarate

To a stirred solution of(S)-tert-butyl-[2-[1-[1-(1,2,3,6,7,8-hexahydrocyclopent[g]indolyl)]]propyl]carbamate(0.31 g, 1.0 mmol) in methanol (5 mL) at 0° C. was added dropwise asolution of hydrogen chloride in dioxan (4 M, 5.0 mL, 20 mmol). Themixture was warmed to room temperature, stirred for 2 h, concentrated invacuo and partitioned between dichloromethane (25 mL) and aqueous sodiumhydroxide solution (5N, 2 mL) in water (10 mL). The separated organicphase was dried (sodium sulfate), concentrated in vacuo and purified bycolumn chromatography [SiO₂, chloroform-methanol (19:1)] to give acolourless oil (0.11 g). The oil was dissolved in hot 2-propanol andadded to a stirred suspension of fumaric acid (0.068 g) in hot2-propanol (2 mL). The solution was cooled to room temperature and theemerging precipitate was collected by filtration, washed with 2-propanoland dried in vacuo to give the product as a white solid (0.11 g, 33%);m.p. 182° C. (dec.). Found: C, 65.09; H, 7.29; N, 8.42%. C₁₄H₂₀N₂.C₄H₄O₄requires: C, 65.04; H, 7.28; N, 8.42%.

Example 9

[2S,3′(R orS)]-1-(3-Ethyl-2,3,7,8-tetrahydrofuro[2,3-g]indol-1-yl)-2-propylaminefumarate; and

Example 10

[2S,3′(S orR)]-1-(3-Ethyl-2,3,7,8-tetrahydrofurol2,3-g]indol-1-yl)2-propylaminefumarate

3-Acetyl-7,8-dihydrofuro[2,3-g]indole

To stirred N,N-dimethylacetamide (2.1 mL) under Ar at 0° C. was addedphosphorous oxychloride (1.0 mL, 10.7 mmol) dropwise over 10 min. Theresultant pale yellow mixture was allowed to warm to ambienttemperature, then a solution of 7,8-dihydrofuro[2,3-g]indole (800 mg,5.0 mmol) in N,N-dimethylacetamide (1.5 mL) was added over 3 min and themixture was stirred for 2 h. The resultant suspension was heated at 65°C. for 30 min, then cooled in an ice-water bath. Ice (10 g) was addedportionwise to the stirred mixture followed by the cautious addition of20% aqueous sodium hydroxide (10 mL), then water (15 mL). The resultantmixture was heated to reflux for 10 min then cooled to room temperatureand diluted with ice-water (50 mL). The suspension was filtered-off anddried to give the crude product (870 mg, 86%) as a beige solid.Recrystallisation from hot ether (10 mL) afforded the product (746 mg,74%) as a cream-coloured solid: m.p. 233-234.5° C.; NMR (400 MHz,DMSO-d₆) δ_(H) 2.41 (3H, s), 3.32 (1H, 2H, t, J 8.5 Hz), 4.58 (2H, t, J8.5 Hz), 6.69 (1H, d, J 8.5 Hz), 7.91 (1H, d, J 8.5 Hz), 8.18 (1H, d,J3.0 Hz) and 11.76(1H, br s).

3-Ethyl-7,8-dihydrofuro[2,3-g]indole

To a stirred mixture of 3-acetyl-7,8-dihydrofuro[2,3-g]indole (721 mg,3.58 mmol) in tetrahydrofuran (25 mL) under an atmosphere of Ar atambient temperature was added, over 5 min, borane (1.0 M in THF; 18 mL,18 mmol). The resultant mixture was stirred at ambient temperature for30 min, then heated to reflux for 2 h before cooling to roomtemperature. Acetone (25 mL) was added and the mixture was heated toreflux for a further 30 min. The mixture was cooled to room temperaturethen all solvent was removed in vacuo. Methanol (40 mL) was added, andthe mixture was again heated to reflux for 30 min, then cooled to roomtemperature followed by solvent removal in vacuo. Purification by flashcolumn chromatography [SiO₂; ethyl acetate-heptane (1:4)] afforded theproduct (302 mg, 45%) as a white solid: m.p. 91-92.5° C.; Found: C,76.90; H, 7.02; N, 7.44%. C₁₂H₁₃NO requires: C, 76.98; H, 7.00; N,7.48%.

(S)-1-[2-(tert-Butoxycarbonylamino)propyl]-3-ethyl-7,8-dihydrofuro[2,3-g]indole

(S)-1-[2-(tert-Butoxycarbonylamino)propyl]-3-ethyl-7,8-dihydrofuro[2,3-g]indolewas prepared according to the method described in Example 1, using3-ethyl-7,8-dihydrofuro[2,3-g]indole (284 mg, 1.52 mmol). Purificationthrough a short plug of silica (dichloromethane eluant) followed bytrituration with hot methanol afforded the product (225 mg, 43%) as awhite solid: m.p. 185-186° C. (dec.); NMR (400 MHz, CDCl₃) δ_(H) 1.11(3H, d, J 6.5 Hz), 1.29 (3H, t, J 7.5 Hz), 1.41 (9H, br s), 2.70 (2H,qd, J 7.5, 1.0 Hz), 3.43-3.68 (2H, m), 3.89-4.05 (2H, m), 4.10-4.53 (2H,m), 4.60-4.67 (2H, m), 6.69 (2H, m) and 7.31 (1H, d, J 8.5 Hz).

(2′S,3R) and(2′S,3S)-1-[2-(tert-Butoxycarbonylamino)propyl]-3-ethyl-2,3,7,8-tetrahydrofuro[2,3-g]indoles

To a stirred solution of(S)-1-[2-(tert-butoxycarbonylamino)propyl]-3-ethyl-7.8-dihydrofuro[2,3-g]indole(209 mg, 0.69 mmol) in acetic acid (20 mL) under Ar at 5° C. was addedsodium cyanoborohydride (130 mg, 2.00 mmol), and the resultant mixturewas stirred at ambient temperature for 16 h. The reaction was pouredonto ice-water (75 mL) and ammonium hydroxide was added portionwise (topH 9-10). The mixture was extracted with chloroform (3×40 mL). Thecombined organic extracts were washed with brine (40 mL), dried (MgSO₄)and the solvent removed in vacuo to afford the crude products (228 mg,109%) as a 2:1 mixture of diastereoisomers [as determined by ¹H-NMR (400MHz)—by integration of the CHCH ₃ doublets].

The crude products were dissolved in dichloromethane (1 mL) and wereseparated into the constituent single diastereomers by repeat injection(50 μL injections) onto a semi-preparative chiral HPLC column [ChiralCelOD, hexane-2-propanol (95:5), 3 mL/min, 210 nm]. This procedure affordedIsomer 1 (95 mg, 45%) as a white solid: LC [ABZ+(15 cm ×4.6 mm; 5 μm);210 nm; 1 mL/min; methanol-10 mM aqueous ammonium acetate solution(80:20)] 99.1% (4.53 min); MS (ES+) m/z 291 [M+H−(CH₃)₂C═CH₂]⁺; andIsomer 2 (50 mg, 24%) as a colourless oil (which slowly crystallised toa white solid): LC [ABZ+(15 cm×4.6 mm; 5 μm); 210 nm; 1 mL/min;methanol-10 mM aqueous ammonium acetate solution (80:20)] 98.0% (4.58min); MS (ES+) m/z 291 [M+H−(CH₃)₂C═CH₂]⁺.

[2S,3(R orS)]-1-(3-Ethyl-2,3,7,8-tetrahydrofuro[2,3-g]indol-1-yl)-2-propylaminefumarate

Salt formation was carried-out according to the method described inExample 1, affording the title compound (76.5 mg, 77%) as a white solid(fumarate): LC [ABZ+(15 cm×4.6 mm; 5 μm); 210 nm; 1 mL/min; methanol-10mM aqueous ammonium acetate solution (70:30)] 98.3% (2.98 min); Found:C, 63.04; H, 7.28; N, 7.79%. C₁₉H₂₆N₂O₅ requires: C, 62.97; H, 7.23; N,7.73%.

[2S,3(S orR)]-1-(3-Ethyl-2,3,7,8-tetrahydrofuro[2,3-g]indol-1-yl)-2-propylaminefumarate

Salt formation was carried-out according to the method described inExample 1, affording the title compound (37.6 mg, 62%) as a white solid(1.5 fumarate): NMR (400 MHz, DMSO) δ_(H) 0.90 (3H, t, J 7.5 Hz); 1.23(3H, d, J 6.5 Hz); 1.36-1.50 (1H, m); 1.65-1.77 (1H, m); 2.93-3.04 (2H,m); 3.08-3.31 (4H, m); 3.32-3.44 (1H, m); 3.45-3.55 (1H, m); 4.36-4.47(2H, m); 6.60 (1H, d, J 7.5 Hz); 6.48 (3H, s); 6.74 (1H, d, J 7.5 Hz)and 2.8-4.6 (very broad hump-NH ₃ ⁺); LC [ABZ+(15 cm×4.6 mm; 5 μm); 210nm; 1 mL/min; methanol-10 mM aqueous ammonium acetate (70:30)] 97% (3.06min).

Example 11

(S)-2-[6-(acetyl)-1-(2,3,6,7,8,9-hexahydro-pyrrolo[2,3-f]quinolinyl)]-2-propylaminefumarate

(R)-1-[1-(1H-Pyrrolo[2,3-f]quinolinyl)]-propan-2-ol

A mixture of sodium hydride (60%, 0.76 g, 18.5 mmol) and tetrahydrofuran(30 mL) was cooled to 0° C. under Ar. A solution of1H-pyrrolo[2,3-f]quinoline (G. Bartoli, G. Palmieri, M. Bosco and R.Dalpozzo, Tetrahedron Letters, 1989, 30, 2129-2132) (2.5 g, 14.8 mmol)and tetrahydrofuran (20 mL) was added and the mixture was left at 0° C.for 1 h. (R)-Propylene oxide (2.1 mL, 30 mmol) was added and the mixturewas left at room temperature for 48 h. Saturated aqueous ammoniumchloride solution (100 mL) was added and the mixture was extracted withether (3×100 mL), the extracts were combined, washed with brine (2×100mL), dried (MgSO₄), concentrated in vacuo and purified by columnchromatography (SiO₂; ether) to give the product (0.61 g, 18% yield) asa pale yellow oil: IR ν_(max) (Nujol)/cm⁻¹ 3106, 1361, 1117, 826, 805,and 731; NMR δ_(H) (400 MHz, CDCl₃) 1.35 (3H, d, J 6.5 Hz), 2.76 (1H,br), 4.33 (1H, m), 4.44 (1H, m), 4.56 (1H, m), 6.64 (1H, d, J 3.0 Hz),7.20 (1H, d, J 3.0 Hz), 7.30 (1H, dd, J 8.5 and 4.5 Hz), 7.71 (1H, d, J9.0 Hz), 7.87 (1H, d, J 9.0 Hz), 8.52 (1H, d, J 8.5 Hz) and 8.67 (1H,m).

(S)-1-(2-Azidopropyl)-1H-pyrrolo[2,3-f]quinoline

A stirred mixture of (R)-1-[1-(1H-pyrrolo[2,3-f]quinolinyl)]-propan-2-ol(0.58 g, 2.6 mmol), dichloromethane (10 mL) and triethylamine (0.4 mL,2.8 mmol) was cooled to 0° C. Methanesulfonyl chloride (0.2 mL, 2.8mmol) was added and the yellow mixture was stirred at room temperaturefor 1 h. Brine (50 mL) was added and the mixture was extracted withdichloromethane (3×50 mL). The extracts were combined, washed with brine(50 mL), dried (MgSO₄) and concentrated in vacuo to give a pale yellowsolid (0.76 g), which was added to a mixture of DMF (10 mL) and sodiumazide (0.3 g, 4.8 mmol). The mixture was heated to 70° C. and stirredfor 16 h then cooled to room temperature. Brine (50 mL) was added andthe mixture was extracted with ether (3×50 mL), the extracts werecombined, washed with brine (50 mL), dried (MgSO₄), concentrated invacuo and purified by column chromatography [SiO₂; ethyl acetate-hexane(1:1)] to give the product (0.32 g, 53% yield) as a pale yellow oil: IRν_(max) (liquid film)/cmν_(max) 2119, 1356, 1259, 826, 807, 734, and696; NMR δ_(H) (400 MHz, CDCl₃) 1.37 (3H, d, J 6.5 Hz), 4.0 (1H, m),4.50 (2H, m), 6.70 (1H, d,J 3.0 Hz), 7.17 (1H, d, J 3.0 Hz), 7.46 (1H,dd,J 8.5 and 4.5 Hz), 7.80 (1H, d, J 9.0 Hz), 7.94 (1H, J 8.5 Hz), 8.47(1H, d, J 8.5 Hz) and 8.85 (1H, d, J 4.5 Hz).

(S)1-[2-(tert-Butoxycarbonylamino)propyl]-1H-pyrrolo[2,3-f]quinoline

A mixture of (S)-1-(2-azidopropyl)-1H-pyrrolo[2,3-f]quinoline (14.9 g,59.4 mmol), ethanol (200 mL) and platinum(IV)oxide (0.5 g) was stirredunder an hydrogen atmosphere for 36 h. The mixture was filtered throughcelite®, washing with diethyl ether (2×200 mL) and the filtrate wasconcentrated in vacuo to give a pale green oil. Water (60 mL) and2-methyl-2-propanol (60 mL) were added, the mixture was stirred at roomtemperature for 10 min then freshly crushed sodium hydroxide (9.4 g,0.23 mol) was added and the mixture was stirred for a further 5 min.Di-tert-butyl dicarbonate (12.8 g, 58.6 mmol) was added and the mixturewas left to stir at room temperature for 16 h. Water (100 mL) was addedand the mixture was extracted with ethyl acetate (3×30 mL), the extractswere combined washed with brine (2 ×), dried (MgSO₄), filtered,concentrated in vacuo and purified by column chromatography [SiO₂; ethylacetate-heptane (1:8)] to give the title compound (10.3 g, 53%) as apale brown solid: m.p. 185° C.; δ_(H) (400 MHz, CDCl₃) 1.13 (3H, s),1.44 (9H, s), 4.16-4.27 (2H, m), 4.49-4.56 (1H, m), 4.91-5.01 (1H, m),6.65-6.66 (1H, d, J 1 Hz), 7.12-7.13 (1H, d, J 2.5 Hz), 7.48-7.54 (1H,m), 7.80-7.82 (1H, d, J 9 Hz), 7.91-7.94 (1H, d, J 9 Hz), 8.83-8.86 (1H,m) and 9.05 (1H, brs).

(S)-1-[2-(tert-Butoxycarbonylamino)propyl]-1H-6,7,8,9-tetrahydro-pyrrolo[2,3-f]quinoline

A mixture of(S)-1-[2-(tert-butoxycarbonylamino)propyl]-1H-pyrrolo[2,3-f]quinoline (5g, 15.4 mmol), 10% palladium on activated carbon (0.5 g) and ethanol (30mL) was shaken under an hydrogen atmosphere (50 psi) for 4 h. Themixture was filtered through celite®, washing with diethyl ether (3×50mL) and concentrated in vacuo to give a green oil. Column chromatography[SiO₂; ethyl acetate-heptane (1:4)] gave the title compound (1.02 g,20%) as a colourless solid: IR ν_(max) (Nujol)/cm⁻¹ 3370, 1690, 1523,1460, 1223, 1173, 1056 and 700; NMR δ_(H) (400 MHz, CDCl₃) 1.08 (3H, d,J 6.5 Hz), 1.39 (9H, s), 2.01-2.07 (2H, m), 3.08-3.21 (2H, m), 3.28-3.30(2H, m), 3.95-4.00 (1H, m), 4.15-4.39 (1H, m), 4.39 (2H, brs), 6.20 (1H,d, J 3.5 Hz), 6.37 (1H, d, J 9 Hz), 6.77 (1H, d, J 3.5 Hz) and 7.21 (1H,d, J 9 Hz).

(S)-6-Acetyl-1-[2-(tert-butoxycarbonylamino)propyl]-1H-6,7,8,9-tetrahydropyrrolo[2,3-f]quinoline

To a stirred mixture of(S)-1-[2-(tert-butoxycarbonylamino)propyl]-1H-6,7,8,9-tetrahydro-pyrrolo[2,3-f]quinoline(0.9 g, 2.7 mmol) and toluene (15 mL) was added acetic anhydride (0.3mL, 3.2 mmol). The mixture was heated under reflux for 1 h, cooled toroom temperature then concentrated in vacuo and purified by columnchromatography [SiO_(2;) ethyl acetate-heptane (1:1)] to give the titlecompound (0.84 g, 84%) as a colourless foam; IR ν_(max) (nujol)/cm⁻¹1706, 1631, 1458, 1378, 1056 and 723; NMR δ_(H) (400 Mz, CDCl₃) 1.09(3H, d, J 6.5 Hz), 1.38 (9H, s), 2.01-2.11 (2H, m), 2.17 (3H, s),3.05-3.10 (1H, m), 3.12-3.18 (1H, m), 3.83-3.86 (2H, m), 3.94-4.09 (1H,m), 4.20-5.07 (3H, m), 6.45-6.46 (1H, m), 6.88-6.90 (1H, m), 6.98-6.99(1H, m) and 7.31-7.36 (1H, d, J 9 Hz).

(S)-6-Acetyl-1-[2-(tert-butoxycarbonylamino)propyl]-1H-2,3,6,7,8,9-hexahydropyrrolo[2,3-f]quinoline

(S)-6-Acetyl-1-[2-(tert-butoxycarbonylamino)propyl]-1H-2,3,6,7,8,9-hexahydropyrrolo[2,3-f]quinolinewas prepared from(S)-6-acetyl-1-[2-(tert-butoxycarbonylamino)propyl]-1H-6,7,8,9-tetrahydropyrrolo[2,3-f]quinolineaccording to the method described in Example 1 to give a pale yellow oil(0.54 g, 91%); IR ν_(max) (DCM smear)/cm⁻¹ 1707, 1633, 1251, 1169 and736; NMR δ_(H) (400 MHz, CDCl₃) 1.26-1.28 (3H, d, J 6 Hz), 1.44 (9H, s),1.83-1.99 (2H, m), 2.17 (3H, s), 2.53-2.71 (2H, m), 2.94-3.26 (4H, m),3.42-3.59 (2H, m), 3.67-3.82 (2H, m), 3.86-3.97 (1H, m), 4.66 (1H, brs),6.49-6.61 (1H, m), and 6.92-6.95 (1H, d, J 8 Hz).

(S)-2-[6-(acetyl)-1-(2,3,6,7,8,9-hexahydro-pyrrolo[2,3-f]quinolinyl)]-2-propylamine fumarate

(S)-2-[6-(acetyl)-1-(2,3,6,7,8,9-hexahydro-pyrrolo[2,3-f]quinolinyl)]-2-propylaminefumarate was prepared from(S)-6-acetyl-1-[2-(tert-butoxycarbonylamino)propyl]-1H-2,3,6,7,8,9-hexahydropyrrolo[2,3-f]quinoline according to the methoddescribed in Example 1 to give the product as a colourless solid (0.37g, 74%): m.p. 230° C. (dec.); NMR δ_(H) (400 MHz, DMSO-d₆) 1.32-1.33(3H, d, J 6.5 Hz), 1.76-1.98 (2H, m), 2.15 (3H, s), 2.61-2.79 (2H, m),2.91-3.78 (XH, m), 6.53 (2H, s), 6.79-6.88 (1H, m) and 7.01-7.03 (lH, d,J 7.5 Hz).

1. A method of treating a condition treatable by agonism of the 5HT2receptor comprising administering a compound of formula (I):

wherein: R₁ and R₂ are independently selected from hydrogen and alkyl;R₃ is alkyl; R4 and R₅ are selected from hydrogen and alkyl; R6 and R₇are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl,amino, alkylamino, dialkylamino, alkoxy, aryloxy, alkylthio,alkylsulfoxyl, alkylsulfonyl, nitro, carbonitrile, carbo-alkoxy,carbo-aryloxy and carboxyl; and A is a 6-membered ring containing oneheteroatom selected from S or O, wherein the atoms of the ring A, otherthan the unsaturated carbon atoms of the phenyl ring to which the ring Ais fused, are saturated or unsaturated, or a pharmaceutically acceptablesalt, addition compound or prodrug thereof.
 2. A method of treatment ofdisorders of the central nervous system; damage to the central nervoussystem; cardiovascular disorders; gastrointestinal disorders; diabetesinsipidus, or sleep apnea comprising administering to a patient in needof such treatment a pharmaceutically effective amount of a compound offormula (I):

wherein: R₁ and R₂ are independently selected from hydrogen and alkyl;R₃ is alkyl; R4 and R₅ are selected from hydrogen and alkyl; R6 and R₇are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl,amino, alkylamino, dialkylamino, alkoxy, aryloxy, alkylthio,alkylsulfoxyl, alkylsulfonyl, nitro, carbonitrile, carbo-alkoxy,carbo-aryloxy and carboxyl; and A is a 6-membered ring containing oneheteroatom selected from S or O, wherein the atoms of the ring A, otherthan the unsaturated carbon atoms of the phenyl ring to which the ring Ais fused, are saturated or unsaturated, or a pharmaceutically acceptablesalt, addition compound or prodrug thereof.
 3. A method according toclaim 2, wherein the disorders of the central nervous system areselected from the group consisting of depression, atypical depression,bipolar disorders, anxiety disorders, obsessive-compulsive disorders,social phobias or panic states, sleep disorders, sexual dysfunction,psychoses, schizophrenia, migraine and other conditions associated withcephalic pain or other pain, raised intracranial pressure, epilepsy,personality disorders, age-related behavioural disorders, behaviouraldisorders associated with dementia, organic mental disorders, mentaldisorders in childhood, aggressivity, age-related memory disorders,chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia,anorexia nervosa and premenstrual tension.
 4. A method according toclaim 2, wherein the damage to the central nervous system is by trauma,stroke, neurodegenerative diseases or toxic or infective CNS diseases.5. A method according to claim 4, wherein said toxic or infective CNSdisease is encephalitis or meningitis.
 6. A method according to claim 2,wherein the cardiovascular disorder is thrombosis.
 7. A method accordingto claim 2, wherein the gastrointestinal disorder is dysfunction ofgastrointestinal motility.
 8. A method of treatment according to claim2, wherein said disorder is obesity.
 9. A method according to claim 2,wherein said treatment is prophylactic treatment.
 10. A method of makinga pharmaceutical composition, comprising combining a compound of formula(I):

wherein: R₁ and R₂ are independently selected from hydrogen and alkyl;R₃ is alkyl; R₄ and R₅ are selected from hydrogen and alkyl; R₆ and R₇are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl,amino, alkylamino, dialkylamino, alkoxy, aryloxy, alkylthio,alkylsulfoxyl, alkylsulfonyl, nitro, carbonitrile, carbo-alkoxy,carbo-aryloxy and carboxyl; and A is a 6-membered ring containing oneheteroatom selected from S or O, wherein the atoms of the ring A, otherthan the unsaturated carbon atoms of the phenyl ring to which the ring Ais fused, are saturated or unsaturated, or a pharmaceutically acceptablesalt, addition compound or prodrug thereof.